Carbidopa levodopa sustained release tablet and preparation method thereof

Abstract

The application belongs to the technical field of pharmaceutical preparations, and specifically provides a carbidopa levodopa sustained-release tablet, which contains carbidopa, levodopa, potassium hydrogen tartrate, a sustained-release material, a binder and a lubricant. The carbidopa in the sustained-release tablet has good stability and is not prone to oxidative degradation, thereby improving the drug efficacy of the carbidopa levodopa sustained-release tablet. In addition, the wet granulation technology is used in the application, the preparation process is simple, the cost is low, and the application is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a carbidopa-levodopa sustained-release tablet. Background Technology

[0002] Parkinson's disease (PD) is a common neurodegenerative disease, also known as "shaking palsy." It is primarily caused by degeneration of the substantia nigra-striatal system in the brain, leading to a deficiency of dopamine and resulting in extrapyramidal dysfunction. Levodopa is currently the most effective drug for treating Parkinson's disease and has a promising market prospect.

[0003] Levodopa is an aromatic amino acid, a white crystalline compound, slightly soluble in water (structure shown below). Levodopa is a precursor to dopamine and is commonly used to treat essential Parkinson's disease and non-drug-induced Parkinson's syndrome. Most of the levodopa absorbed into the bloodstream is decarboxylated by dopa decarboxylase in peripheral tissues to form dopamine. Dopamine does not easily cross the blood-brain barrier; only a small amount of levodopa crosses the blood-brain barrier and enters the brain tissue, where it is converted into dopamine by dopa decarboxylase to exert its therapeutic effect.

[0004] .

[0005] Carbidopa is an inhibitor of aromatic amino acid decarboxylation, a white crystalline compound, slightly soluble in water (structure shown below). Carbidopa does not readily cross the blood-brain barrier and only inhibits the activity of peripheral dopa decarboxylase, making it an important adjunct to levodopa. When carbidopa is used in combination with levodopa, it reduces dopamine production in peripheral tissues, alleviates peripheral adverse reactions, thereby increasing the amount of levodopa entering the brain tissue, raising the concentration of dopamine in the brain, and enhancing the therapeutic effect of levodopa.

[0006] .

[0007] Carbidopa-L-dopa sustained-release tablets are effective in treating Parkinson's disease, but problems still exist. The raw material of carbidopa contains phenolic hydroxyl groups, which are very unstable. They are easily oxidized and decomposed when exposed to air, and are even more unstable in aqueous solutions. This results in a low carbidopa content in carbidopa-L-dopa sustained-release tablets, reducing their efficacy.

[0008] Patent CN103622942A discloses a levodopa / carbidopa compound sustained-release suspension and its preparation method, which improves drug stability by encapsulating the drug in resin; Patent CN109715139A discloses levodopa and carbidopa enteric gel and its usage method for duodenal administration; however, the above methods have relatively complicated preparation processes, the parameters are difficult to control during the preparation process, and the production cost is high, making them unsuitable for large-scale production.

[0009] Patent CN105362252A discloses a sustained-release capsule containing levodopa and carbidopa and its preparation method. The contents of the sustained-release capsule are sustained-release microspheres, which prolong the drug action time. However, the parameters of the microsphere preparation process are difficult to control, and the drug loading of the microspheres needs to be strictly controlled.

[0010] Patent CN103191094A discloses a carbidopa-levodopa sustained-release tablet and its preparation method, which uses a one-step granulation and coating technology. However, its formulation is relatively complex, the drug release is rapid, the drug action time is short, and carbidopa is subject to oxidative degradation after prolonged storage, which affects the efficacy.

[0011] Existing technologies for producing carbidopa-levodopa extended-release tablets often result in a decrease in carbidopa content during stability studies due to the rapid oxidation and decomposition of carbidopa, thus affecting the therapeutic effect of levodopa. Therefore, developing a carbidopa-levodopa extended-release tablet with good carbidopa stability remains a pressing issue. Summary of the Invention

[0012] Addressing the shortcomings and research challenges of existing technologies, this invention provides a carbidopa-levodopa sustained-release tablet comprising carbidopa, levodopa, potassium hydrogen tartrate, a sustained-release material, a binder, and a lubricant. The carbidopa content in this tablet is stable and resistant to oxidative degradation, thus improving the efficacy of the carbidopa-levodopa sustained-release tablet.

[0013] Specifically, the technical solution of the present invention is as follows:

[0014] A carbidopa-levodopa sustained-release tablet comprises carbidopa, levodopa, potassium bitartrate, sustained-release material, binder, and lubricant.

[0015] The sustained-release material is one or two of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose E5, sodium carboxymethyl cellulose, and ethyl cellulose; preferably, the sustained-release material is hydroxypropyl methylcellulose K4M or hydroxypropyl methylcellulose K15M.

[0016] The adhesive is one or two of hydroxypropyl cellulose L, hydroxypropyl cellulose H, and polyethylene glycol; preferably, the adhesive is hydroxypropyl cellulose L or hydroxypropyl cellulose H.

[0017] The lubricant is selected from one or two of magnesium stearate, sodium stearate fumarate, and silicon dioxide.

[0018] The carbidopa-levodopa extended-release tablets contain the following components by weight percentage:

[0019] Preferably, the mass percentage of potassium hydrogen tartrate is 2-5%.

[0020] Preferably, the sustained-release material has a mass percentage of 2-6%.

[0021] Preferably, the adhesive has a mass percentage of 10%.

[0022] Preferably, the carbidopa has a mass percentage of 16% and the levodopa has a mass percentage of 65%.

[0023] Preferably, the carbidopa-levodopa extended-release tablet contains the following components by weight percentage:

[0024] Another aspect of the present invention provides a method for preparing the carbidopa-levodopa sustained-release tablets, comprising the following steps:

[0025] (1) Prepare an adhesive solution by mixing the adhesive with water;

[0026] (2) Sieve and mix carbidopa, levodopa, potassium bitartrate, and slow-release material, and then wet granulate.

[0027] (3) Add lubricant and mix evenly. Compress the powder directly into tablets.

[0028] Preferably, the concentration of the adhesive in step (1) of the preparation method is 8%-9%.

[0029] Preferably, the preparation method of the carbidopa-levodopa sustained-release tablet includes the following steps:

[0030] (1) Prepare an 8%-9% adhesive solution with water;

[0031] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and slow-release material through a 10-20 mesh sieve and wet granulate;

[0032] (3) Add lubricant and mix evenly. Compress the powder directly into tablets.

[0033] Compared with the prior art, the advantages of the present invention are as follows:

[0034] (1) The present invention uses potassium hydrogen tartrate as an additive, which can effectively prevent the oxidative decomposition of carbidopa, improve the stability of carbidopa in sustained-release tablets, and improve the efficacy of carbidopa-levodopa sustained-release tablets.

[0035] (2) The present invention uses wet granulation technology, which has a simple preparation process, low cost, and is suitable for industrial production. Attached Figure Description

[0036] Figure 1Example 1: Pharmacokinetic curves of the carbidopa-levodopa extended-release tablets prepared in Comparative Example 1 and the commercially available Sinemet® extended-release tablets. Detailed Implementation

[0037] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0038] Example 1

[0039] prescription:

[0040] Preparation method:

[0041] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose L with water.

[0042] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and hydroxypropyl methylcellulose K4M through a 20-mesh sieve and wet granulate.

[0043] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0044] Example 2

[0045] prescription:

[0046] Preparation method:

[0047] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose H with water.

[0048] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and hydroxypropyl methylcellulose K15M through a 20-mesh sieve and wet granulate.

[0049] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0050] Example 3

[0051] prescription:

[0052] Preparation method:

[0053] (1) Prepare a 9% adhesive solution by mixing hydroxypropyl cellulose H with water.

[0054] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and hydroxypropyl methylcellulose K4M through a 10-mesh sieve and wet granulate.

[0055] (3) Add sodium stearate and mix well. Compress the powder directly into tablets.

[0056] Example 4

[0057] prescription:

[0058] Preparation method:

[0059] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose L with water.

[0060] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and hydroxypropyl methylcellulose K4M through a 20-mesh sieve and wet granulate.

[0061] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0062] Example 5

[0063] prescription:

[0064] Preparation method:

[0065] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose L with water.

[0066] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate, and hydroxypropyl methylcellulose E5 through a 20-mesh sieve and wet granulate.

[0067] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0068] Example 6

[0069] prescription:

[0070] Preparation method:

[0071] (1) Prepare an 8% adhesive solution by mixing polyethylene glycol with water.

[0072] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and ethyl cellulose through a 20-mesh sieve and wet granulate.

[0073] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0074] Example 7

[0075] prescription:

[0076] Preparation method:

[0077] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose L with water.

[0078] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and hydroxypropyl methylcellulose K4M through a 20-mesh sieve and wet granulate.

[0079] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0080] Example 8

[0081] prescription:

[0082] Preparation method:

[0083] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose L with water.

[0084] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and hydroxypropyl methylcellulose K4M through a 20-mesh sieve and wet granulate.

[0085] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0086] Example 9

[0087] prescription:

[0088] Preparation method:

[0089] (1) Prepare a 5% adhesive solution of povidone with water.

[0090] (2) Mix carbidopa, levodopa, potassium hydrogen tartrate and ethyl cellulose through a 40-mesh sieve and wet granulate.

[0091] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0092] Comparative Example 1

[0093] prescription:

[0094] Preparation method:

[0095] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose L with water.

[0096] (2) Mix carbidopa, levodopa and hydroxypropyl methylcellulose K4M through a 20-mesh sieve and wet granulate.

[0097] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0098] Comparative Example 2

[0099] prescription:

[0100] Preparation method:

[0101] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose L with water.

[0102] (2) Mix carbidopa, levodopa, vitamin C and hydroxypropyl methylcellulose K4M through a 20-mesh sieve and wet granulate.

[0103] (3) Add magnesium stearate and mix evenly. Compress the powder directly into tablets.

[0104] Comparative Example 3

[0105] prescription:

[0106] Preparation method:

[0107] (1) Prepare an 8% adhesive solution by mixing hydroxypropyl cellulose L with water.

[0108] (2) Mix carbidopa, levodopa, sodium bisulfite and hydroxypropyl methylcellulose K4M through a 20-mesh sieve and wet granulate.

[0109] (3) Add lubricant and mix evenly. Compress the powder directly into tablets.

[0110] Comparative Example 4

[0111] prescription:

[0112] Preparation method:

[0113] Weigh out hydroxypropyl methylcellulose E15 and Opadryl according to the prescription, dissolve them in 95% ethanol and water to prepare the coating solution; mix carbidopa, levodopa, microcrystalline cellulose, hydroxypropyl methylcellulose K15M and micronized silica gel evenly, add the above coating solution for fluidized bed granulation, dry, add added magnesium stearate, mix evenly, and compress into tablets using a conventional tableting machine.

[0114] Verification Implementation Examples

[0115] 1. Dissolution test

[0116] The dissolution rate of the carbidopa and levodopa sustained-release tablets obtained in Examples 1-9 and Comparative Examples 1-4 was determined using the following method. 0.1N HCl was used as the dissolution medium, with a volume of 900 mL and a rotation speed of 50 rpm, using a paddle method. Sufficient amounts of the solution were collected at 30, 60, 150, and 240 min, and filtered to obtain the test solution. Separately, 32 mg of carbidopa reference standard and 100 mg of levodopa reference standard were weighed and placed in a 100 mL volumetric flask. 0.1N hydrochloric acid solution was added, and the solution was dissolved using sonication. The solution was then diluted to the mark with 0.1N hydrochloric acid solution to obtain the reference solution. The dissolution rate of both the test solution and the reference solution was determined by HPLC. Specific results are shown in Table 1.

[0117] Table 1 Dissolution rate of Carbidopa-L-dopa Extended-Release Tablets

[0118] The experimental results show that the carbidopa-levodopa sustained-release tablets prepared in this invention have sustained-release characteristics, releasing more than 85% within 0-4 hours. In contrast, the sustained-release tablets prepared in Comparative Example 4 release the drug too quickly, have a short duration of action, and exhibit poor sustained-release effect.

[0119] 2. Stability assessment of carbidopa

[0120] The carbidopa levodopa sustained-release tablets prepared in Examples 1-9 and Comparative Examples 1-4 of this invention were placed in a constant temperature and humidity chamber at 40℃±2℃ and 75%±5% relative humidity for 6 months. The content was measured at 0 days and 6 months, respectively. The test results are shown in Table 2.

[0121] Table 2. Results of the stability study of carbidopa

[0122] The sustained-release tablets prepared using the formulation of this invention exhibit good carbidopa stability, with minimal change in carbidopa content after 6 months of accelerated storage. In contrast, comparative examples 1 and 4 without potassium bitartrate and comparative examples 2 and 3 using other additives showed significantly reduced carbidopa content.

[0123] 3. Measurement of blood drug concentration

[0124] A single-dose, two-period crossover trial was conducted. Nine male Beagle dogs were randomly divided into three groups (A, B, and C), with three dogs in each group. Dogs were fasted for 12 hours prior to the trial. Group A received two tablets of the example drug orally, Group B received two tablets of the control group, and Group C received two tablets of Sinemet® extended-release tablets (carbidopa 50mg / levodopa 200mg). Food was given four hours later. After a washout period of more than one week, the Beagle dogs were crossover-administered the medication.

[0125] Two ml of blood was collected from the forelimb vein 1 hour before administration and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, and 24 hours after administration. After plasma processing, plasma drug concentrations were determined using liquid chromatography-triple quadrupole mass spectrometry (LC-MS / MS). The drug-time curves are shown below. Figure 1 As shown, the area under the curve (AUC) of the drug in Example 1 is significantly higher than that of Comparative Example 1 and Sinemet® sustained-release tablets. The Example 1 can maintain a relatively stable blood drug concentration for a longer period of time, and has high bioavailability.

Claims

1. A carbidopa-levodopa sustained-release tablet, characterized in that, It contains the following components by weight percentage: 15-17% carbidopa, 60-70% levodopa, 2-7% potassium bitartrate, 1-10% sustained-release material, 5-15% binder, and 0.5-2% lubricant.

2. The carbidopa-levodopa sustained-release tablet according to claim 1, characterized in that, The sustained-release material is selected from one or two of hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose E5, sodium carboxymethyl cellulose, and ethyl cellulose.

3. The carbidopa-levodopa sustained-release tablet according to claim 1, characterized in that, The adhesive is selected from one or two of hydroxypropyl cellulose L, hydroxypropyl cellulose H, and polyethylene glycol.

4. The carbidopa-L-dopa sustained-release tablet according to claim 1, characterized in that, The lubricant is selected from one or two of magnesium stearate, sodium stearate fumarate, and silicon dioxide.

5. The carbidopa-levodopa sustained-release tablet according to claim 1, characterized in that, The mass percentage of potassium bitartrate is 2-5%.

6. The carbidopa-L-dopa sustained-release tablet according to claim 1, characterized in that, The sustained-release material has a mass percentage of 2-6%.

7. The carbidopa-levodopa sustained-release tablet according to claim 1, characterized in that, The adhesive has a mass percentage of 10%.

8. A method for preparing a carbidopa-L-dopa sustained-release tablet according to any one of claims 1-7, characterized in that, Includes the following steps: 1) Prepare an adhesive solution by mixing the adhesive with water; 2) Sieve and mix carbidopa, levodopa, potassium bitartrate, and the slow-release material, and then perform wet granulation; 3) Add lubricant, mix well, and compress into tablets.

9. The method for preparing carbidopa-L-dopa sustained-release tablets according to claim 8, characterized in that, Includes the following steps: 1) Prepare an 8%-9% adhesive solution using water; 2) Mix carbidopa, levodopa, potassium bitartrate, and the slow-release material through a 10-20 mesh sieve, and then perform wet granulation; 3) Add lubricant, mix well, and compress into tablets.

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