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WO2025097792A1 - Comprimé à trois couches de carbidopa-lévodopa et son procédé de préparation - Google Patents

Comprimé à trois couches de carbidopa-lévodopa et son procédé de préparation Download PDF

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Publication number
WO2025097792A1
WO2025097792A1 PCT/CN2024/101511 CN2024101511W WO2025097792A1 WO 2025097792 A1 WO2025097792 A1 WO 2025097792A1 CN 2024101511 W CN2024101511 W CN 2024101511W WO 2025097792 A1 WO2025097792 A1 WO 2025097792A1
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Prior art keywords
layer
release layer
levodopa
carbidopa
sustained
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Chinese (zh)
Inventor
张海龙
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Changsha King Eagle Med Technology Co Ltd
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Changsha King Eagle Med 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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 the field of medicine, and in particular to a carbendazim tri-layer tablet and a preparation method thereof.
  • Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease.
  • Levodopa is the gold standard drug for the treatment of Parkinson's disease and is often used in combination with the peripheral decarboxylase inhibitor carbidopa.
  • Levodopa is a prodrug of dopamine and is metabolized to dopamine by decarboxylase in the body, which has the effect of replenishing dopamine in the brain.
  • the role of carbidopa is to inhibit the activity of peripheral dopa decarboxylase, so that levodopa can enter the blood-brain barrier in its original form and then be metabolized to dopamine by decarboxylase to exert its drug effect.
  • Parkinson's disease cannot be cured at present, the main way to alleviate symptoms is to supplement dopamine in the brain. Therefore, long-term use of levodopa is required.
  • patients often show some movement complications, including the end-of-dose effect of symptom recurrence before the next medication, drug-induced dyskinesias manifested as uncontrolled abnormal movements, and the "on-off" effect manifested as unpredictable fluctuations in motor ability.
  • drug-induced dyskinesias manifested as uncontrolled abnormal movements
  • the "on-off" effect manifested as unpredictable fluctuations in motor ability.
  • the occurrence of such motor complications can be slowed down by controlling stable plasma levodopa concentrations.
  • the medication is required to take effect quickly to restore the patient's ability to move.
  • the medication is required to have the characteristic of long-term stable drug release.
  • Carbidopa sustained-release formulations have been marketed both at home and abroad, but patients still take the medicine three times a day or more.
  • Carbidopa double-layer gastric retention sustained-release tablets have also been reported in the prior art.
  • CN114615972A discloses a permeable, floating gastric retention formulation with a complex preparation process
  • CN102202656A discloses a medicinal oral formulation for prolonged release of levodopa and carbidopa, but the onset time and sustained-release effect have not been significantly improved
  • CN116098883A discloses a carbidopa gastric retention sustained-release preparation, which is a combination of a quick-release layer and a sustained-release layer, and can achieve twice a day.
  • the sustained-release layer needs to expand to a larger volume and have a certain rigidity while providing drug release, so that the tablet can be retained in the stomach.
  • a certain contradiction between the release of the drug and the expansion of the tablet that is, a larger expansion volume and sufficient tablet rigidity cannot be achieved at an appropriate drug release rate, and increasing the expansion volume and rigidity of the tablet will delay the drug release rate, so that the blood drug concentration cannot reach the therapeutic window.
  • Such a contradiction limits the gastric retention performance of carbidopa, thereby affecting the sustained-release effect. Therefore, it is necessary in the art to provide a carbidopa sustained-release tablet with a low frequency of medication and long-term stable drug release characteristics.
  • the present invention provides a three-layer tablet of carbendazim, which can be taken twice a day, has better gastric retention effect, more moderate blood drug concentration in human body and more lasting sustained release effect.
  • the present invention provides a carbidopa three-layer tablet, which comprises a quick-release layer, a sustained-release layer and a swelling layer, wherein the quick-release layer comprises 15-20% carbidopa, 65-73% levodopa, 5-10% binder, 3-9% gel and 0.5-1% lubricant by weight percentage; the sustained-release layer comprises 10-15% carbidopa, 45-55% levodopa, 5-10% binder, 20-35% gel and 0.5-1% lubricant; the swelling layer comprises 40-60% filler, 15-30% disintegrant, 15-30% gel and 0.5-2% lubricant.
  • the purpose of the immediate-release layer is to quickly increase the blood drug concentration, but releasing levodopa too quickly can easily cause gastrointestinal discomfort, leading to adverse reactions such as nausea and vomiting in patients. Therefore, a small amount of gel material needs to be added to the immediate-release layer to control the drug to be completely released within 0.5h-1h; the purpose of the sustained-release layer is to provide a long-term stable blood drug concentration, so an appropriate amount of gel material needs to be added to the sustained-release layer to control the drug to be completely released within 6h; the purpose of the expansion layer is to increase the expansion volume of the tablet without affecting the drug release, and to ensure that the tablet expands to exceed the average size of the pylorus (12.8mm) within 1h.
  • the weight percentage of carbidopa in the immediate-release layer is 15-20%, for example, 15%, 17%, 19% or 20%, as well as specific values between the above values. Due to space limitations and for the sake of simplicity, the present invention will no longer exhaustively list the specific values included in the range.
  • the weight percentage of levodopa in the immediate-release layer is 65-73%, for example, 65%, 67%, 69%, 72% or 73%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
  • the weight percentage of the quick-release layer adhesive is 5-10%, for example, it can be 5%, 7%, 9% or 10%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
  • the weight percentage of the quick-release layer gel is 3-9%, for example, 3%, 6%, 8% or 9%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
  • the weight percentage of the quick-release layer lubricant is 0.5-1%, for example, 0.5%, 0.7%, 0.9%. Or 1%, as well as specific point values between the above point values. Due to space limitations and for the sake of brevity, the present invention will no longer exhaustively list the specific point values included in the said range.
  • the weight percentage of carbidopa in the sustained-release layer is 10-15%, for example, 10%, 12%, 13% or 15%, as well as specific values between the above values. Due to space limitations and for the sake of simplicity, the present invention will no longer exhaustively list the specific values included in the range.
  • the weight percentage of levodopa in the sustained-release layer is 45-55%, for example, it can be 45%, 47%, 49%, 53% or 55%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
  • the weight percentage of the sustained-release layer adhesive is 5-10%, for example, 5%, 7%, 9% or 10%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
  • the weight percentage of the sustained-release layer gel is 20-35%, for example, it can be 20%, 25%, 29% or 35%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
  • the weight percentage of the sustained-release layer lubricant is 0.5-1%, for example, it can be 0.5%, 0.7%, 0.9% or 1%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
  • the weight percentage of the expansion layer filler is 40-60%, for example, it can be 40%, 44%, 48%, 54%, 58% or 60%, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
  • the weight percentage of the expansion layer disintegrant is 15-30%, for example, it can be 15%, 17%, 19%, 23%, 26%, 29% or 30%, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
  • the weight percentage of the expansion layer gel is 15-30%, for example, it can be 15%, 17%, 19%, 23%, 26%, 29% or 30%, as well as specific values between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range.
  • the weight percentage of the expansion layer lubricant is 0.5-2%, for example, 0.5%, 0.9%, 1.5% or 2%, and specific values between the above points are not included in the present invention due to space limitations and for the sake of simplicity. The specific point values included in the range are exhaustively listed.
  • the binder in the immediate-release layer includes any one of methylcellulose, hydroxypropyl cellulose, hypromellose, and povidone, or a combination of at least two thereof.
  • the gel in the immediate-release layer includes any one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyoxyethylene, carbomer, gelatin, or a combination of at least two thereof.
  • the lubricant in the immediate-release layer includes any one of magnesium stearate, talc, and micro-powdered silica gel, or a combination of at least two of them.
  • the binder in the sustained-release layer includes any one of methyl cellulose, hydroxypropyl cellulose, hypromellose, and povidone, or a combination of at least two thereof.
  • the gelling agent in the sustained-release layer includes any one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyoxyethylene, carbomer, gelatin, or a combination of at least two thereof.
  • the lubricant in the sustained-release layer includes any one of magnesium stearate, talc, and micro-powdered silica gel, or a combination of at least two of them.
  • the disintegrant in the expansion layer includes any one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose, or a combination of at least two thereof.
  • the lubricant in the expansion layer includes any one of magnesium stearate, talc, and micro-powdered silica gel, or a combination of at least two of them.
  • the filler in the expansion layer includes any one of microcrystalline cellulose, polyvinyl acetate, and a polyvinyl acetate-povidone mixture, or a combination of at least two thereof.
  • the filler in the expansion layer is a polyvinyl acetate-povidone mixture.
  • the filler in the expansion layer is selected from water-insoluble microcrystalline cellulose, polyvinyl acetate, and polyvinyl acetate-povidone mixture, the purpose of which is to provide sufficient structural support for the expansion layer after expansion to ensure that the expansion layer will not dissolve and shrink before the drug is completely released.
  • the gelling agent in the expansion layer comprises carbomer.
  • the gelling agent in the expansion layer further comprises any one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyoxyethylene, or a combination of at least two thereof.
  • the weight ratio of the carbomer to other gelling agents is 5:1 to 6:1; and other gelling agents are hydroxypropyl cellulose and/or hydroxypropyl methylcellulose and/or polyoxyethylene.
  • the weight ratio of the carbomer to hydroxypropyl cellulose and/or hydroxypropyl methylcellulose and/or polyoxyethylene is 5:1 to 6:1, for example, 5:1, 5.5:1 or 6:1, as well as specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values included in the range.
  • the gelling agent in the expansion layer is carbomer and hypromellose.
  • the weight ratio of carbomer to hydroxypropyl methylcellulose in the expansion layer is 5:1 to 6:1.
  • the expansion volume is the largest, but the rigidity is insufficient, so it needs to be used in combination with other gelling agents.
  • the carbidopa-levodopa three-layer tablet comprises, by weight percentage, 16-18% carbidopa, 67-70% levodopa, 6-8% binder, 6-8% gel and 0.6-0.8% lubricant in the immediate-release layer; 11-13% carbidopa, 48-52% levodopa, 6-9% binder, 25-29% gel and 0.7-0.9% lubricant in the sustained-release layer; and 45-55% filler, 20-25% disintegrant, 20-28% gel and 1-2% lubricant in the expansion layer.
  • the carbidopa-levodopa three-layer tablet comprises, by weight percentage, 17% carbidopa, 69% levodopa, 7% binder, 7% gel and 0.7% lubricant in the immediate-release layer; 13% carbidopa, 50% levodopa, 8% binder, 28% gel and 0.8% lubricant in the sustained-release layer; and 50% filler, 23% disintegrant, 25% gel and 1.7% lubricant in the expansion layer.
  • Another aspect of the present invention provides a method for preparing carbocycline trilayer tablets, the method comprising granulating the active ingredient, mixing the active ingredient particles obtained after granulation with the auxiliary materials of the immediate release layer and the sustained release layer respectively, and placing the mixed materials into a tablet press for tableting.
  • the first layer of the tableting material is an expansion layer
  • the second layer is a sustained-release layer
  • the third layer is an immediate-release layer
  • the expansion layer of the three-layer tablet of carbodiol can expand to a size exceeding the average size of the pylorus within 1 hour. (12.8mm), and the tablet rigidity can maintain more than 100gf within 6h;
  • the carbocycline-levodopa three-layer tablets of the present invention can be retained in the stomach of beagle dogs for more than 10 hours;
  • the carboplatin three-layer tablets of the present invention are shown in the human drug release curve to provide a more sustained blood drug concentration.
  • FIG1 is a comparison diagram of the expansion width of the carbodiol three-layer tablets prepared in Examples 1 to 4;
  • FIG2 is a comparison chart of the rigidity strength of the three-layer carbodiol tablets prepared in Examples 1 to 4;
  • FIG3 is a comparison diagram of the expansion width of the carbodiol three-layer tablets prepared in Examples 5 to 12;
  • FIG4 is a comparison chart of the rigidity strength of the three-layer carbodiol tablets prepared in Examples 5 to 12;
  • FIG5 is an in vitro dissolution curve of carbidopa in the carbidopa-levodopa three-layer tablets prepared in Examples 13 to 15;
  • FIG6 is an in vitro dissolution curve of levodopa in the card levodopa three-layer tablets prepared in Examples 13 to 15;
  • FIG7 is an in vitro dissolution curve of carbidopa in the carbidopa-levodopa three-layer tablets prepared in Examples 16 to 18;
  • FIG8 is an in vitro dissolution curve of levodopa in the card levodopa three-layer tablets prepared in Examples 16 to 18;
  • FIG9 is an in vitro dissolution curve of carbidopa in the carbidopa-levodopa three-layer tablets prepared in Example 19 and the reference preparation;
  • FIG10 is an in vitro dissolution curve of levodopa in the card levodopa three-layer tablets prepared in Example 19 and the reference preparation;
  • FIG11 is an X-ray image of a beagle dog in the beagle dog gastric retention experiment in Example 22;
  • FIG12 is a drug-time curve of carbidopa obtained from a comparative study of human pharmacokinetics in Example 23;
  • FIG. 13 is a drug-time curve of levodopa obtained from the comparative human pharmacokinetics study in Example 23.
  • compositions comprising, “including,” “having,” “containing,” or any other variation thereof, are intended to cover a non-exclusive inclusion.
  • a composition, process, method, article, or apparatus that comprises the listed elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
  • the features defined as “first” or “second” may include one or more of the features explicitly or implicitly, and are used to distinguish and describe the features, without distinction of order or importance.
  • “plurality” means two or more.
  • Tablet pressing Put the mixed materials into the tablet press, start the tablet press to prepare tablets, and finally control the tablet hardness to 80 ⁇ 20N.
  • Tablet pressing Put the mixed materials into the tablet press, start the tablet press to prepare tablets, and finally control the tablet hardness to 90 ⁇ 20N.
  • Immediate-release layer Weigh the materials according to the prescription table of Examples 13-15, mix them for 10 minutes using a two-dimensional mixer, and set aside after mixing evenly.
  • Expansion layer Weigh the materials according to the prescription table of Example 7, mix them for 10 minutes using a two-dimensional mixer, and set aside after mixing evenly.
  • the mixed materials are placed in a tablet press, wherein the first layer is an expansion layer and the second layer is an immediate release layer.
  • the tablet press is started to prepare a double-layer tablet, and the tablet hardness of the double-layer tablet is controlled to be 180 ⁇ 20N.
  • the granulation method is consistent with Examples 13-15.
  • Sustained-release layer Weigh the materials according to the prescription table of Examples 16-18, mix them for 10 minutes using a two-dimensional mixer, and set aside after mixing evenly.
  • Expansion layer Weigh the materials according to the prescription table of Example 7, mix them for 10 minutes using a two-dimensional mixer, and set aside after mixing evenly.
  • Tablet pressing Put the mixed materials into the tablet press, where the first layer is the expansion layer and the second layer is the sustained-release layer. Start the tablet press to prepare double-layer tablets, and control the tablet hardness of the double-layer tablets to 200 ⁇ 20N.
  • the granulation method is consistent with Examples 13-15.
  • the first layer of materials is the expansion layer
  • the second layer of materials is the sustained-release layer
  • the third layer of materials is the immediate-release layer.
  • Swelling performance mainly includes two aspects: swelling size and tablet rigidity.
  • Swelling size It is generally believed that in order to achieve gastric retention, the shorter axis (width) of the tablet needs to swell to 12 mm, preferably 13 mm, within 1 hour.
  • the expanded width of the tablet is measured using a vernier caliper.
  • Tablet rigidity Gastric retentive preparations require sufficient structural strength to withstand antral force to avoid being crushed and emptied by the stomach. According to existing literature (Assessment of antral grinding of a model solid meal with echo-planar imaging), the maximum antral force of the human body is about 0.65N (65gf), so the maximum pressure that the expansion layer can withstand before the drug is fully released should be higher than 65gf, preferably higher than 100gf.
  • the structural strength of the tablet is tested by pressing down on the center of the tablet using a texture analyzer. Select TA/5 cylindrical probe, target mode is "pressing down”, test type is "deformation”, and target value is "50%".
  • the in vitro swelling performance was tested using a disintegrator, whose reciprocating motion could simulate the gastric emptying movement of the stomach; the medium selected was 0.1M HCl solution to simulate gastric fluid; and the experimental temperature was controlled at 37°C.
  • the in vitro expansion performance test results of Examples 5 to 12 show that the tablet width of Examples 5 and 6 expands slowly, and the tablet width cannot expand to 12.8 mm within one hour; the rigidity of the tablets prepared in Examples 9 and 10 cannot be maintained above 100 gf within 6 hours; therefore, when the gel is a compound of carbomer and hypromellose, the weight ratio of the two is preferably 5:1-6:1; when the gel is a combination of carbomer and other gels except hypromellose, the weight ratio of the two is also preferably 5:1-6:1; within the above weight ratio range, the expansion layer can expand to exceed the average size of the pylorus (12.8 mm) within 1 hour, and the tablet rigidity can be maintained above 100 gf within 6 hours.
  • Carbopol tri-layer tablets prepared in Examples 13-15 10 min, 20 min, 30 min, 45 min, 60 min, 90 min;
  • the in vitro dissolution results of the immediate-release layer show that the card left double
  • the release rate of the three-layer tablet of dopa is slow.
  • the release rate of the three-layer tablet of carbodopa prepared in Examples 13 and 14 is more suitable.
  • the amount of the gelling agent polyoxyethylene in the immediate release layer is preferably 3-7%. When other gelling agents are selected in the immediate release layer, the amount is preferably 3-9%.
  • the results of in vitro dissolution of the sustained-release layer show that the release rate of the three-layer tablets of carbodiol prepared in Example 16 is faster, and the release rate of the three-layer tablets of carbodiol prepared in Examples 17 and 18 is more appropriate.
  • the amount of the gelling agent polyoxyethylene in the sustained-release layer is preferably 26-32%. When other gelling agents are selected in the sustained-release layer, the amount is preferably 20-35%.
  • Beagles are the most commonly used experimental animals. They can ingest human-scale dosage forms and have good gastrointestinal physiological characteristics, which can predict the performance of dosage forms in humans.
  • the 50 mg polyvinyl acetate-povidone mixture in the expansion layer was replaced with barium sulfate to conduct a beagle gastric retention experiment.
  • the specific experimental method is to orally gavage the preparation to beagle dogs, and take X-rays at 0h, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, and 12h.
  • the results show that the three-layer film can be retained in the stomach of beagle dogs for more than 10 hours, and some development points can still be observed in the stomach at 12h.
  • Example 18 In order to locate the tablets using X-rays smoothly, the preparation used in Example 18 is based on the prescription of Example 15, with part of the polyvinyl acetate-povidone mixture replaced by barium sulfate for easy development.
  • the polyvinyl acetate-povidone mixture only plays a role of skeleton filling in the expansion layer and does not affect the expansion performance of the tablets.
  • barium sulfate is an inert substance with stable material and chemical properties. A small amount of barium sulfate does not affect the expansion of the tablets. Therefore, replacing a small part of the polyvinyl acetate-povidone mixture with barium sulfate will not have a significant impact on the result data of the gastric retention experiment.
  • a randomized, open, two-period crossover, single-dose, postprandial dosing design was used to evaluate the carbidopa trilayer tablets (test preparation specifications: carbidopa 100 mg, levodopa 400 mg) prepared in Example 15 and the carbidopa sustained-release tablets (control preparation specifications: carbidopa 50 mg, levodopa 200 mg, trade name: ) in healthy subjects.
  • Blood samples were collected before administration (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, and 24 h after administration (a total of 15 blood sampling points).
  • Non-compartmental pharmacokinetic analysis was used to determine the following parameters of levodopa and carbidopa: The area under the curve for dosing to the last time point (AUC 0-t ), the AUC for dosing to infinity (AUC 0- ⁇ ), the maximum concentration (C max ), the time to reach maximum concentration (T max ), and the terminal half-life (t 1/2 ).
  • Example 15 can provide a more sustained blood drug concentration than the reference preparation (Sinamine).
  • the median Tmax of carbidopa in Example 15 is 8.00h (4.00h, 12.00h), and the median Tmax of levodopa is 5.5h (2.00h, 10.00h), while the median Tmax of carbidopa in the reference preparation is 5.00h (4.00h, 6.00h), and the median Tmax of levodopa is 4h (3.00h, 6.00h), which indicates that Example 15 has a longer effective sustained release time than Sinamine.
  • the Cmax of carbidopa and levodopa in Example 15 are 67.777 ⁇ 23.922 (35.30) and 1711.083 ⁇ 306.839 (17.93), respectively, and the Cmax of carbidopa and levodopa in the reference preparation are 51.838 ⁇ 13.268 (25.60) and 1520.558 ⁇ 451.776 (29.71), respectively.
  • the Cmax of the drug in Example 15 is slightly higher than that in the reference preparation, but the difference is not large, and there is no safety risk.
  • Example 15 shows that the gastric retentive three-layer tablet provided by the present invention can provide a relatively stable levodopa concentration for a long time, which has obvious advantages over the reference preparation.
  • CN116098883A discloses a carbendazim gastric retention sustained-release preparation.
  • Carbendazim double-layer tablets were prepared according to the prescription and preparation method of Example 1 of the patent.
  • the human pharmacokinetic study was carried out using the method of Example 19 of the present invention.
  • the pharmacokinetic data and drug-time curve of the carbendazim three-layer tablets prepared in Example 15 were compared. The results showed that the carbendazim three-layer tablets prepared in Example 15 could provide a relatively stable levodopa concentration for a relatively long time, and had a relatively obvious advantage.
  • FIG7A-B shows the plasma concentration-time curves of levodopa (FIG. 7A) and carbidopa (FIG. 7B) of LC4SL, LC6BL and Mylan dosage forms in human subjects.
  • the Mylan dosage form is The drug-time curve of the Mylan dosage form in FIG7A is consistent with FIG13 of the present application, indicating that the pharmacokinetic behaviors of carbidopa and levodopa in the two experiments are similar.

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  • Biomedical Technology (AREA)
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Abstract

L'invention concerne un comprimé à trois couches de carbidopa-lévodopa, comprenant une couche à libération immédiate, une couche à libération prolongée et une couche d'expansion, la couche à libération immédiate comprenant, en pourcentage en poids, 15% à 20% de carbidopa, 65% à 73% de lévodopa, 5% à 10% d'un adhésif, 3% à 9% d'un gel, et 0,5% à 1% d'un lubrifiant ; la couche à libération prolongée comprend, en pourcentage en poids, 10% à 15% de carbidopa, 45% à 55% de lévodopa, 5% à 10% d'un adhésif, 20% à 35% d'un gel, et 0,5% à 1% d'un lubrifiant ; et la couche d'expansion comprend, en pourcentage en poids, 40% à 60% d'une charge, 15% à 30% d'un agent de désintégration, 15% à 30% d'un gel, et 0,5% à 2% d'un lubrifiant. La couche d'expansion du comprimé à trois couches de carbidopa-levodopa peut être expansée pour dépasser la taille pylorique moyenne (12.8 mm) en 1 h, et la rigidité du comprimé peut être maintenue à 100 gf ou plus en 6 h. Le comprimé peut être retenu dans l'estomac des chiens beagle pendant 10 h ou plus. Une courbe de libération de médicament corporel humain montre que le comprimé peut fournir une concentration plasmatique plus soutenue.
PCT/CN2024/101511 2023-11-10 2024-06-26 Comprimé à trois couches de carbidopa-lévodopa et son procédé de préparation Pending WO2025097792A1 (fr)

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CN117599009A (zh) * 2023-11-10 2024-02-27 长沙晶易医药科技股份有限公司 一种卡左双多巴三层片及其制备方法
CN119925282A (zh) * 2024-12-25 2025-05-06 原研药港生命科学(辽宁)集团有限公司 一种胃滞留双层缓释片及其制备方法和应用

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WO2000038650A1 (fr) * 1998-12-23 2000-07-06 Alza Corporation Forme posologique a retention gastrique possedant des couches multiples
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