Preparation method of compound levodopa and benserazide dual-release preparation and the preparation

Abstract

The present invention provides a preparation method for a compound levodopa and benserazide hydrochloride dual-release preparation. By means of the addition method of benserazide hydrochloride, the wet granulation of the first group of sustained-release materials, and the moisture control during dry screening in the preparation process of the drug-containing sustained-release layer granules, the influence of moisture and temperature on benserazide hydrochloride is reduced, the degradation of benserazide hydrochloride is reduced, and the stability of the compound levodopa and benserazide hydrochloride dual-release preparation is improved. The present invention provides a compound levodopa and benserazide hydrochloride dual-release preparation, which adopts the design of a double-layer tablet of a drug-containing immediate-release layer and an adjacent drug-containing sustained-release layer. After the patient takes the medicine, the drug can take effect quickly; and the drug release can be stably controlled to maintain long-term effectiveness, thereby reducing the number of times the patient takes the medicine, keeping the blood drug concentration stable, and increasing the patient's compliance.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and specifically relates to a preparation method of a compound levodopa-benserazide dual-release preparation and its preparation. Background Art

[0002] Levodopa-benserazide was developed and marketed by Roche Pharmaceuticals in 1970 for the treatment of Parkinson's disease. Levodopa-benserazide tablets are compound preparations prepared from levodopa and benserazide hydrochloride in a ratio of 4:1.

[0003] Research shows that patients with Parkinson's syndrome lack the neurotransmitter dopamine in the basal ganglia. Levodopa can cross the blood-brain barrier and enter the central nervous system to serve as a direct metabolic precursor of dopamine. However, levodopa is rapidly decarboxylated outside the brain and converted into dopamine, resulting in a large waste of levodopa and frequent occurrence of adverse reactions. Benserazide hydrochloride can inhibit the decarboxylation of levodopa outside the brain and enhance the therapeutic effect.

[0004] Levodopa-benserazide tablets were launched in China in 2003, and the marketed product name is The specification of Madopar is 250 mg (levodopa 200 mg, benserazide 50 mg), which is taken 30 minutes before meals or 1 hour after meals. The initial recommended dose is 0.5 tablets of Madopar three times a day, and then the daily dose is increased by 0.5 tablets per week until the therapeutic dose suitable for the patient is reached. In the stable state, the patient takes 2 - 4 tablets orally per day, divided into 3 - 4 times, and the daily dose does not exceed 5 tablets. The frequency of medication is high, and the patient's compliance with taking medicine is poor.

[0005] The prior art US4424235A discloses a hydrodynamically balanced controlled-release composition containing levodopa and a decarboxylase inhibitor, which improves the level of levodopa in the blood and provides a more sustained blood level. However, this effect is limited, especially in terms of increasing the initial blood level of levodopa.

[0006] Due to the poor stability of benserazide hydrochloride, there are many factors affecting its stability, such as the moisture content of raw and auxiliary materials, pH value, temperature, etc. Benserazide hydrochloride is prone to hydrolysis, and the existing production processes cannot cover the influencing factors affecting the stability of benserazide hydrochloride. For example, the prior art CN114224878A discloses a compound drug for the treatment of Parkinson's disease. In the process of preparing the levodopa-benserazide compound drug, the total amount of benserazide hydrochloride and the total amount of mannitol are sieved, stirred and mixed into a second mixture, and the remaining ethanol solution of polyvinylpyrrolidone is added to prepare a second wet granule. Wet granulation is not conducive to the stability of benserazide hydrochloride and is prone to hydrolysis. Therefore, the stability of the prepared levodopa-benserazide tablets is also relatively poor. So, it is necessary to study a new preparation method and process for levodopa-benserazide tablets to improve the stability of levodopa-benserazide tablet products. Summary of the Invention

[0007] In view of the technical problems that the compound levodopa and benserazide tablets prepared by the existing preparation method have poor stability, and the existing compound levodopa and benserazide tablets require frequent administration, resulting in poor medication compliance of patients, the present invention provides a preparation method and a preparation of a compound levodopa and benserazide dual-release preparation. By changing the API mixing method, adding benserazide hydrochloride externally, reducing the degradation of benserazide hydrochloride, and performing wet granulation on the first group of sustained-release materials and controlling the particle moisture, the stability of the compound levodopa and benserazide sustained-release preparation product is improved. The specific technical solutions are as follows:

[0008] In the first aspect, the present invention provides a preparation method of a compound levodopa and benserazide dual-release preparation, comprising the following steps:

[0009] S1. Preparation of drug-containing immediate-release layer granules: Weigh appropriate amounts of levodopa, the first group of fillers, disintegrants, and binders, and perform wet granulation with an organic acid solution; perform wet screening after wet granulation; dry the wet granules; perform dry screening after drying; after dry screening, add lubricants and the second group of fillers for premixing, and then add an appropriate amount of benserazide hydrochloride for total mixing to obtain drug-containing immediate-release layer granules;

[0010] S2. Preparation of drug-containing sustained-release layer granules: Weigh appropriate amounts of levodopa, the first group of sustained-release materials, fillers, and binders, and perform wet granulation with an organic acid solution; perform wet screening after wet granulation; dry the wet granules; perform dry screening after drying; after dry screening, add lubricants, glidants, and the second group of sustained-release materials for premixing, and then add an appropriate amount of benserazide hydrochloride for total mixing to obtain drug-containing sustained-release layer granules;

[0011] S3. Preparation of the compound levodopa and benserazide dual-release preparation core tablets: Weigh an appropriate amount of the drug-containing sustained-release layer granules and place them in the die of a tableting machine for pre-pressing; then weigh an appropriate amount of the drug-containing immediate-release layer granules and place them in the die of the tableting machine to press into the compound levodopa and benserazide dual-release preparation core tablets;

[0012] S4. Coating: Use a coating solution to coat the compound levodopa and benserazide dual-release preparation core tablets obtained in step S3 to obtain the compound levodopa and benserazide dual-release preparation.

[0013] Further, in the preparation of the drug-containing immediate-release layer granules in S1, the content of the weighed levodopa is 6% - 10%; the content of the first group of fillers is 4% - 10%; the content of the disintegrant is 0.1% - 2%; the content of the binder is 0.5% - 3%; the content of the organic acid is 0.1% - 0.5%; the content of the lubricant is 0.1% - 1%; the content of the second group of fillers is 2% - 5%; the content of benserazide hydrochloride is 1% - 3%; the first group of fillers and the second group of fillers may be the same or different;

[0014] In some embodiments, preferably, in the preparation of the S1 drug-containing immediate-release layer granules, the content of levodopa is 6% - 9%; the content of the first group of fillers is 4% - 8%; the content of the disintegrant is 0.6% - 0.8%; the content of the binder is 0.5% - 1.2%; the content of the organic acid is 0.1% - 0.2%; the content of the lubricant is 0.15% - 0.3%; the content of the second group of fillers is 2% - 5%; the content of benserazide hydrochloride is 1.5% - 3%;

[0015] Furthermore, in the preparation of the S2 drug-containing sustained-release layer granules, the weighed content of levodopa is 14% - 20%; the content of the first group of sustained-release materials is 22% - 35%; the content of the filler is 17% - 25%; the content of the binder is 1% - 5%; the content of the organic acid is 0.1% - 1.5%; the content of the lubricant is 0.1% - 2%; the content of the glidant is 0.2 - 1%; the content of the second group of sustained-release materials is 3% - 5%; the content of benserazide hydrochloride is 4% - 7%; the first group of sustained-release materials and the second group of sustained-release materials are the same or different;

[0016] In some embodiments, preferably, in the preparation of the S2 drug-containing sustained-release layer granules, the content of levodopa is 14% - 16%; the content of the first group of sustained-release materials is 25% - 30%; the content of the filler is 19% - 22%; the content of the binder is 3% - 5%; the content of the organic acid is 0.3% - 0.7%; the content of the lubricant is 0.6% - 1%; the content of the glidant is 0.5% - 1%; the content of the second group of sustained-release materials is 3% - 5%; the content of benserazide hydrochloride is 4% - 5%;

[0017] Furthermore, in the preparation of the S3 compound levodopa and benserazide dual-release tablets, the mass ratio of the drug-containing sustained-release layer granules to the drug-containing immediate-release layer granules is 3 - 4:1;

[0018] Furthermore, in S1 and S2, the wet granules are dried, and the water content after drying of the wet granules does not exceed 3%.

[0019] Furthermore, in S1 and S2, the particle size of benserazide hydrochloride does not exceed 0.425 mm;

[0020] Further, in S1 and S2, the organic acid is selected from one or more of the crystals of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, glutamic acid or aspartic acid; the sustained-release material is selected from one or more of hydroxypropyl methylcellulose, xanthan gum, sodium alginate, polyethylene oxide; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, cross-linked povidone and pregelatinized starch; the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch or pregelatinized starch; the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone; the glidant is selected from one or more of colloidal silica, magnesium stearate; the lubricant is selected from one or more of talc powder, colloidal silica, sodium stearyl fumarate or magnesium stearate;

[0021] Further, in S1, the first group of fillers is added for wet granulation; after dry screening, the second group of fillers is added for premixing; the first group of fillers is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch or pregelatinized starch; the second group of sustained-release materials is selected from one or two of microcrystalline cellulose and mannitol;

[0022] Further, in S2, the first group of sustained-release materials is added for wet granulation; after dry screening, the second group of sustained-release materials is added for premixing; the first group of sustained-release materials is selected from one or more of hydroxypropyl methylcellulose, xanthan gum, sodium alginate, and the second group of sustained-release materials is selected from one or two of sodium alginate and polyethylene oxide.

[0023] In some embodiments, preferably, the organic acid is preferably tartaric acid; the sustained-release material is preferably hydroxypropyl methylcellulose, sodium alginate and polyethylene oxide; the disintegrant is preferably cross-linked carboxymethyl cellulose sodium or low-substituted hydroxypropyl cellulose; the filler is preferably microcrystalline cellulose; the binder is preferably hydroxypropyl methylcellulose; the glidant is preferably colloidal silica; the lubricant is preferably magnesium stearate or talc powder;

[0024] Further, in S4, the coating solution is prepared from a film-forming material, a light-shielding agent, a plasticizer, an anti-sticking agent, and a colorant; the coating weight gain is 2% - 5%;

[0025] The coating weight gain refers to the percentage of the mass of the dried coating film in the total mass of the compound levodopa and carbidopa sustained-release preparation.

[0026] The film-forming material is polyvinyl alcohol, the light-shielding agent is titanium dioxide, the plasticizer is polyethylene glycol, the anti-sticking agent is talc powder, and the colorant is iron oxide;

[0027] In the coating solution, the content of polyvinyl alcohol is 1% - 2%, the content of titanium dioxide is 0.5% - 1.0%, the content of polyethylene glycol is 0.5% - 0.6%, the content of talc powder is 0.3% - 0.5%, and the content of iron oxide is 0.003% - 0.007%.

[0028] In a second aspect, the present invention provides a compound levodopa and benserazide hydrochloride dual-release preparation, which can be prepared by the preparation method described in the first aspect. The compound levodopa and benserazide hydrochloride dual-release preparation is composed of a drug-containing immediate-release layer containing levodopa and benserazide hydrochloride and an adjacent drug-containing sustained-release layer containing levodopa and benserazide hydrochloride;

[0029] Furthermore, the drug-containing immediate-release layer further includes an organic acid, a filler, a binder, a disintegrant, and a glidant; the drug-containing sustained-release layer further includes an organic acid, a sustained-release material, a filler, a binder, a glidant, and a lubricant;

[0030] In the compound levodopa and benserazide hydrochloride dual-release preparation, the content of levodopa is 20-30%, the content of benserazide hydrochloride is 5-10%, the content of organic acid is 0.2-2.0%, the content of the sustained-release material is 25-40%, the content of the disintegrant is 0.1-2%, the content of the filler is 23-40%, the content of the binder is 1.5-8%, the content of the glidant is 0.2-1%, and the content of the lubricant is 0.2-3%;

[0031] Preferably, in the compound levodopa and benserazide hydrochloride dual-release preparation, the content of levodopa is preferably 20-25%, the content of benserazide hydrochloride is preferably 5-8%, the content of organic acid is preferably 0.2-1%, the content of the sustained-release material is preferably 30-40%, the content of the disintegrant is preferably 0.5-1%, the content of the filler is preferably 25-30%, the content of the binder is preferably 3-5%, the content of the glidant is preferably 0.5-1%, and the content of the lubricant is preferably 0.5-1.5%;

[0032] Furthermore, the organic acid is selected from one or more of crystals of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, glutamic acid, or aspartic acid; the sustained-release material is selected from one or more of hydroxypropyl methylcellulose, xanthan gum, sodium alginate, and polyethylene oxide; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, cross-linked povidone, and pregelatinized starch; the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, or pregelatinized starch; the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone; the glidant is selected from one or more of colloidal silicon dioxide and magnesium stearate; the lubricant is selected from one or more of talc, colloidal silicon dioxide, sodium stearyl fumarate, or magnesium stearate;

[0033] Preferably, the organic acid is preferably tartaric acid; the sustained-release material is preferably hydroxypropyl methylcellulose, sodium alginate, and polyethylene oxide; the disintegrant is preferably cross-linked carboxymethyl cellulose sodium or low-substituted hydroxypropyl cellulose; the filler is preferably microcrystalline cellulose; the binder is preferably hydroxypropyl methylcellulose; the glidant is preferably colloidal silicon dioxide; the lubricant is preferably magnesium stearate or talc;

[0034] The "content" of each component in the first aspect and the second aspect refers to the percentage of the mass of each component in the total mass of the compound levodopa and benserazide hydrochloride dual-release preparation.

[0035] For the compound levodopa and benserazide hydrochloride dual-release preparation prepared by the preparation method of the first aspect or the compound levodopa and benserazide hydrochloride dual-release preparation provided by the second aspect, the initial dose during patient treatment is 300 mg / 75 mg (large specification), and the daily dose is increased by 100 mg / 25 mg (small specification) every week thereafter until the treatment dose suitable for the patient is reached. The maximum dose is 800 / 200 mg. After the patient takes the medicine, it can achieve a rapid onset of action as fast as the commercially available ordinary tablets; it can also maintain long-term effectiveness by stably controlling drug release. By adjusting the drug specification, reducing the number of daily doses, keeping the blood drug concentration stable, and increasing patient compliance.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] The present invention provides a preparation method of a compound levodopa and benserazide hydrochloride dual-release preparation. During the preparation process of the drug-containing rapid-release layer granules, the required prescription amounts of levodopa, the first group of fillers, disintegrants, and binders are wet granulated with tartaric acid solution, wet screened through a sieve, dried, and after dry screening, lubricants and the second group of fillers are added for premixing, and then benserazide hydrochloride is added for total mixing; during the preparation process of the drug-containing sustained-release layer granules, the required prescription amounts of levodopa, the first group of sustained-release materials, fillers, and binders are wet granulated with tartaric acid solution, wet screened through a sieve, dried, and after dry screening, lubricants, glidants, and the second group of sustained-release materials are added for premixing, and then benserazide hydrochloride is added for total mixing.

[0038] In the preparation of the drug-containing rapid-release layer granules and the drug-containing sustained-release layer granules, benserazide hydrochloride is not wet granulated and is added for total mixing only after premixing; during the preparation process of the drug-containing sustained-release layer granules, the first group of sustained-release materials are wet granulated together with levodopa and other excipients, and the moisture content of the dry screening is controlled; through the special addition method of benserazide hydrochloride, the wet granulation of the first group of sustained-release materials, and the moisture content control of the dry screening during the preparation process of the drug-containing sustained-release layer granules, the influence of moisture and temperature on benserazide hydrochloride is reduced, the degradation of benserazide hydrochloride is reduced, the stability of the compound levodopa and benserazide hydrochloride dual-release preparation obtained by the preparation is improved, and thus it can be stored in a high-density polyethylene bottle without using a relatively expensive outer package for storage, reducing the packaging cost.

[0039] The present invention provides a compound levodopa and benserazide dual-release preparation, which adopts the design of a bilayer tablet with a drug-containing immediate-release layer and an adjacent drug-containing sustained-release layer, combining the advantages of immediate-release and sustained-release dosage forms. After the patient takes the medicine, the drug can not only take effect as quickly as the commercially available ordinary tablet, but also maintain long-term effectiveness by stably controlling the drug release. By adjusting the API specifications, the number of daily doses for the patient can be reduced, the blood drug concentration can be kept stable, and the patient compliance can be increased. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The present invention will be further described in detail below in conjunction with the drawings and preferred embodiments. However, those skilled in the art will understand that these drawings are only drawn for the purpose of explaining the preferred embodiments and should not be construed as limiting the scope of the present invention. In addition, unless otherwise specified, the drawings only schematically show the composition or structure of the described object and may include exaggerated displays, and the drawings are not necessarily drawn to scale.

[0041] Figure 1 Figure of the preparation method of the compound levodopa and benserazide dual-release preparation in Example 1;

[0042] Figure 2 Figure of the dissolution test results of benserazide hydrochloride in Example 4 and Comparative Example 5;

[0043] Figure 3 Figure of the dissolution test results of levodopa in Example 4 and Comparative Example 5;

[0044] Figure 4 Schematic diagram of the structure of the compound levodopa and benserazide dual-release preparation in Example 7. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0045] The following will be described in detail in conjunction with the attached Figures 1 to 4 , the present invention will be described in detail.

[0046] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with the drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0047] The quality standard of the compound levodopa and benserazide dual-release preparation is shown in Table 1.

[0048] Table 1 Quality standard of the compound levodopa and benserazide dual-release preparation

[0049]

[0050]

[0051] Preparation method of the compound levodopa and benserazide dual-release preparation in Example 1

[0052] Example 1 of the present invention provides a preparation method of a compound levodopa and benserazide dual-release preparation, as Figure 1 shown, including:

[0053] S1. Preparation of drug-containing immediate-release layer granules: Weigh 92 g of levodopa, 97.2 g of microcrystalline cellulose PH101, 9.5 g of low-substituted hydroxypropyl cellulose, and 15 g of hypromellose E5, add an appropriate amount of tartaric acid solution (containing 1.6 g of tartaric acid), and perform wet granulation through a 60-mesh sieve. The liquid addition time of the tartaric acid solution during the wet granulation process is 0 - 3 min, the stirring speed is 4 - 8 r / s, the shear speed is 5 - 20 r / s, the mixing time of raw and auxiliary materials is 5 min, and the wet granulation time is 0.5 - 3 min;

[0054] Perform wet screening through a sieve with a motor frequency of 5 Hz and a pore size of 2.0 mm, and the particle size of the wet screening does not exceed 2.0 mm;

[0055] Dry in an oven at 55 - 65 °C, and control the moisture content not to exceed 3%;

[0056] After drying, perform dry screening through a sieve with a motor frequency of 5 Hz and a pore size of 1.0 mm, and the particle size of the dry screening does not exceed 1.0 mm;

[0057] After dry screening, add 3 g of talc powder and 31.7 g of microcrystalline cellulose PH102 that have passed through a 40-mesh sieve for premixing; after premixing, add 30 g of benserazide hydrochloride, and the particle size of benserazide hydrochloride does not exceed 0.425 mm, and perform total mixing. The rotation speed of the total mixing is 12 rmp, and the total mixing time is 7 min to obtain the drug-containing immediate-release layer granules;

[0058] S2. Preparation of drug-containing sustained-release layer granules: Weigh 190 g of levodopa, 280 g of microcrystalline cellulose, 105 g of sodium alginate, 103 g of hypromellose K100M, 134 g of hypromellose K200M, and 42 g of polyvinylpyrrolidone K30, add an appropriate amount of tartaric acid solution (containing 9 g of tartaric acid), and perform wet granulation through a 60-mesh sieve. The liquid addition time of the tartaric acid solution during the wet granulation process is 0.5 - 3 min, the stirring speed is 4 - 8 r / s, the shear speed is 5 - 20 r / s, the mixing time of raw and auxiliary materials is 5 min, and the wet granulation time is 0.5 - 3 min;

[0059] Perform wet screening through a sieve with a motor frequency of 5 Hz and a pore size of 2.0 mm, and the particle size of the wet screening does not exceed 2.0 mm;

[0060] Dry in a fluidized bed with an inlet air temperature of 50 - 70 °C, the inlet air volume is 5 - 30 Hz, and control the moisture content not to exceed 3%;

[0061] After drying, dry screening is carried out through a sieve with a mesh size of 1.5 mm at a motor frequency of 5 Hz, and the particle size of dry screening does not exceed 1.5 mm; after dry screening, 53 g of polyoxyethylene, 12 g of talc, and 10 g of colloidal silicon dioxide passing through a 40-mesh sieve are added for premixing; after premixing, 62 g of benserazide hydrochloride passing through a 40-mesh sieve is added, and the particle size of benserazide hydrochloride does not exceed 0.425 mm, and then total mixing is carried out. The rotation speed of total mixing is 15 rpm, and the total mixing time is 3 min to obtain drug-containing sustained-release layer granules;

[0062] S3. Preparation of compound levodopa and benserazide double-release preparation plain tablets: Weigh 1000 mg of drug-containing sustained-release layer granules and place them in the punch die of a tableting machine for pre-pressing; then weigh 280 mg of drug-containing immediate-release layer granules and place them in the punch die of a tableting machine to press into compound levodopa and benserazide double-release preparation plain tablets;

[0063] S4. Coating: Using a coating solution, coat the compound levodopa and benserazide double-release preparation plain tablets obtained in step S3 to obtain compound levodopa and benserazide double-release preparations.

[0064] The coating solution is prepared from polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, yellow iron oxide, and red iron oxide, and the coating weight gain is 37.2 mg.

[0065] The compound levodopa and benserazide double-release preparations obtained in S4 are detected, and the detection results are within the quality standard range of the compound levodopa and benserazide double-release preparations.

[0066] Example 2 and Comparative Example 1 investigate the addition method of benserazide hydrochloride

[0067] There are 2 ways to add benserazide hydrochloride. In Example 2, benserazide hydrochloride is added to the immediate-release layer and the sustained-release layer respectively after wet granulation (referred to as the external addition method), and the experimental process is the same as that of Example 1;

[0068] In Comparative Example 1, benserazide hydrochloride is wet granulated together with levodopa and other excipients (referred to as the internal addition method), and the rest of the experimental process is the same as that of Example 1. The types and addition amounts of each raw material and excipient in Example 2 and Comparative Example 1 are shown in Table 3.

[0069] Table 3 Materials list of Example 2 and Comparative Example 1

[0070]

[0071]

[0072] The compound levodopa and benserazide double-release preparations obtained by adding benserazide hydrochloride through the external addition method and the internal addition method respectively are detected for the content of benserazide hydrochloride in the sustained-release layer, and the detection results are shown in Table 4.

[0073] Table 4 Detection results of compound levodopa and benserazide double-release preparations obtained by different addition methods of benserazide hydrochloride

[0074] Product parameters Test results (%) Content of benserazide hydrochloride in the sustained-release layer of Example 2 97.80 Content of benserazide hydrochloride in the sustained-release layer of Comparative Example 1 87.20

[0075] As can be seen from Table 4, in the compound levodopa and benserazide hydrochloride dual-release preparation obtained by the external addition method, the material content of benserazide hydrochloride in the sustained-release layer reaches 97.8%, which is qualified; while in the compound levodopa and benserazide hydrochloride dual-release preparation obtained by the internal addition method, the material content of benserazide hydrochloride in the sustained-release layer is only 87.20%, which is unqualified. Therefore, in the preparation method of the compound levodopa and benserazide hydrochloride dual-release preparation, it is advisable to add benserazide hydrochloride to the immediate-release layer and the sustained-release layer respectively after premixing, that is, by the external addition method. Since benserazide hydrochloride is unstable, by the internal addition method, that is, wet granulating benserazide hydrochloride with levodopa together, it will cause the decomposition of benserazide hydrochloride and the reduction of its content.

[0076] Example 3 and Comparative Example 2 investigated the effect of wet granulation of the first group of sustained-release materials on the preparation of the compound levodopa and benserazide hydrochloride dual-release preparation

[0077] In Example 3, the first group of sustained-release materials was wet granulated together with levodopa and other excipients, and the experimental process was the same as that of Example 1;

[0078] In Comparative Example 2, the first group of sustained-release materials was not wet granulated together with levodopa and other excipients, and the premixed materials were added after dry screening, and the effect on the content of benserazide hydrochloride in the sustained-release layer was investigated. The remaining experimental process was the same as that of Example 1.

[0079] The types and addition amounts of the original materials and excipients in Example 3 and Comparative Example 2 are shown in Table 4.

[0080] Table 5 Materials of Example 3 and Comparative Example 2

[0081]

[0082]

[0083] The compound levodopa and benserazide hydrochloride dual-release preparations obtained by wet granulating and not wet granulating the first group of sustained-release materials were respectively tested for the content of benserazide hydrochloride in the sustained-release layer, and the test results are shown in Table 6.

[0084] Table 6 Test Results of the Compound Levodopa and Benserazide Hydrochloride Dual-Release Preparations Obtained by Wet Granulating and Not Wet Granulating the First Group of Sustained-Release Materials

[0085] Product parameters Test results (%) Content of benserazide hydrochloride in the sustained-release layer of Example 3 98.2 Content of benserazide hydrochloride in the sustained-release layer of Comparative Example 2 91.7

[0086] As can be seen from Table 6, in the compound levodopa and benserazide hydrochloride dual-release preparation obtained by wet granulation of the first group of sustained-release materials, the material content of benserazide hydrochloride in the sustained-release layer reached 98.2%, which was qualified; while in the compound levodopa and benserazide hydrochloride dual-release preparation obtained without wet granulation of the first group of sustained-release materials, the material content of benserazide hydrochloride in the sustained-release layer was only 87.2%, which was unqualified. Therefore, in the preparation method of the compound levodopa and benserazide hydrochloride dual-release preparation, it is advisable to use the first group of sustained-release materials to carry out wet granulation together with levodopa and other excipients for the preparation of the drug-containing sustained-release layer.

[0087] The reason for the above results is that during the preparation of the drug-containing sustained-release layer, the first group of sustained-release materials are wet granulated together with levodopa and other excipients. After wet screening, drying and dry screening will be carried out, so as to reduce the moisture in the dry screening, and reduce the hydrolysis effect of moisture on benserazide hydrochloride added after premixing.

[0088] Example 2 and Comparative Example 3 investigated the influence of the types of the second group of fillers in the drug-containing rapid-release layer on the preparation of the compound levodopa and benserazide hydrochloride dual-release preparation

[0089] Comparative Example 3 used corn starch as the second group of fillers to investigate the influence of different second group of fillers on the appearance and friability of the compound levodopa and benserazide hydrochloride dual-release preparation obtained. The experimental process was the same as that of Example 1. The material table of Comparative Example 3 using corn starch as the second group of fillers is shown in Table 7.

[0090] Table 7 Material Table of Comparative Example 3

[0091]

[0092]

[0093] The appearance of the compound levodopa and benserazide hydrochloride dual-release preparations prepared using microcrystalline cellulose and corn starch as the second group of fillers respectively was observed and the friability was detected. The detection results are shown in Table 8.

[0094] Table 8 Detection Results of the Influence of the Types of the Second Group of Fillers in the Drug-containing Rapid-release Layer on the Appearance and Friability of the Compound Levodopa and Benserazide Hydrochloride Dual-release Preparation

[0095]

[0096]

[0097] As can be seen from Table 8, for the compound levodopa and benserazide hydrochloride dual-release preparation prepared using microcrystalline cellulose as the second group of fillers, the appearance was normal, and the friability was 0.08%, which was qualified; while for the compound levodopa and benserazide hydrochloride dual-release preparation prepared using corn starch as the second group of fillers, the appearance had serious chipping, and the friability was 10.5%, which was unqualified. Therefore, microcrystalline cellulose is preferably used as the second group of fillers in the preparation method of the compound levodopa and benserazide hydrochloride dual-release preparation.

[0098] Example 4 and Comparative Example 4 investigated the influence of the moisture content of the dry granulation of the drug-containing sustained-release layer on the preparation of the compound levodopa and benserazide hydrochloride dual-release preparation.

[0099] During the preparation of the drug-containing sustained-release layer in Example 4, levodopa, the first group of sustained-release materials, fillers, and binders were wet granulated with tartaric acid solution and then dried. The moisture content of the dry granulation was controlled to be ≤2%. The experimental process was the same as that in Example 1.

[0100] During the preparation of the drug-containing sustained-release layer in Comparative Example 4, levodopa, the first group of sustained-release materials, fillers, and binders were not wet granulated, and the moisture content was not controlled. The detected moisture content was 8%. The remaining experimental process was the same as that in Example 1. The influence of controlling and not controlling the moisture content on the content of benserazide hydrochloride in the sustained-release layer of the compound levodopa and benserazide hydrochloride dual-release preparation obtained was investigated. The material lists of Example 4 and Comparative Example 4 are shown in Table 9.

[0101] Table 9 Material lists of Example 4 and Comparative Example 4

[0102]

[0103]

[0104] The content of benserazide hydrochloride in the sustained-release layer of the compound levodopa and benserazide hydrochloride dual-release preparations prepared by controlling the moisture content in Example 4 and not controlling the moisture content in Comparative Example 4 was detected. The detection results are shown in Table 10.

[0105] Table 10 Detection results of the influence of moisture content on the content of benserazide hydrochloride in the sustained-release layer of the compound levodopa and benserazide hydrochloride dual-release preparation

[0106] Product parameters Test results (%) Content of benserazide hydrochloride in the sustained-release layer of Example 4 95.2 Content of benserazide hydrochloride in the sustained-release layer of Comparative Example 4 92.56

[0107] As can be seen from Table 10, the content of benserazide hydrochloride in the sustained-release layer of the compound levodopa and benserazide hydrochloride dual-release preparation prepared by controlling the moisture content in Example 4 was 95.2%, which was qualified; while the content of benserazide hydrochloride in the sustained-release layer of the compound levodopa and benserazide hydrochloride dual-release preparation prepared without controlling the moisture content in Comparative Example 4 was 92.56%, which was unqualified. Therefore, it is necessary to control the moisture content of the dry granulation after wet granulation during the preparation of the compound levodopa and benserazide hydrochloride dual-release preparation.

[0108] The reason for the above results is that benserazide hydrochloride is unstable, and with a high moisture content, benserazide hydrochloride is prone to decomposition.

[0109] Example 4 and Comparative Example 5 investigated the influence of the first group of sustained-release materials in the drug-containing sustained-release layer on the preparation of the compound levodopa and benserazide hydrochloride dual-release preparation.

[0110] In Example 4, sodium alginate, hypromellose K100M, and hypromellose K200M were used as the first group of sustained-release materials. The experimental process was the same as that in Example 1.

[0111] In Comparative Example 5, sodium alginate, hypromellose K100M, and hypromellose K15M were used as the first group of sustained-release materials. The material composition and dosage are shown in Table 11, and the experimental process was the same as that of Example 1.

[0112] Table 11 Material Table of Comparative Example 5

[0113]

[0114] For the compound levodopa and benserazide hydrochloride dual-release preparations prepared in Example 4 using sodium alginate, hypromellose K100M, and hypromellose K200M as the first group of sustained-release materials, and Comparative Example 5 using sodium alginate, hypromellose K100M, and hypromellose K15M as the first group of sustained-release materials, the dissolution degrees of levodopa and benserazide hydrochloride were detected, as Figures 2 to 3 shown.

[0115] It can be Figures 2 to 3 seen that for the compound levodopa and benserazide hydrochloride dual-release preparation prepared using sodium alginate, hypromellose K100M, and hypromellose K200M as the first group of sustained-release materials, the dissolution degree of benserazide hydrochloride at 4 hours was 63.9%, and the dissolution degree at 16 hours was 88.4%; the dissolution degree of levodopa at 4 hours was 54.9%, and the dissolution degree at 16 hours was 89.5%.

[0116] For the compound levodopa and benserazide hydrochloride dual-release preparations prepared using sodium alginate, hypromellose K100M, and hypromellose K15M as another first group of sustained-release materials respectively, the dissolution degree of benserazide hydrochloride at 4 hours was 90%, and the dissolution degree at 16 hours was 94.3%; the dissolution degree of levodopa at 4 hours was 58.6%, and the dissolution degree at 16 hours was 89.8%.

[0117] For the compound levodopa and benserazide hydrochloride dual-release preparation prepared in Example 4, the dissolution degrees of both benserazide hydrochloride and levodopa were qualified, indicating that hypromellose K200M is the preferred sustained-release material.

[0118] Example 5 and Comparative Example 6 investigated the influence of organic acids on the preparation of compound levodopa and benserazide hydrochloride dual-release preparations

[0119] In Example 5, the rapid-release layer and the sustained-release layer were wet granulated with a normal prescription amount of tartaric acid solution; tartaric acid was not used in the materials of Comparative Example 6; the preparation methods of the compound levodopa and benserazide hydrochloride dual-release preparations from the two groups of materials were the same as those of Example 1. The impurity contents in the compound levodopa and benserazide hydrochloride dual-release preparations prepared from the two groups of materials were investigated. The material compositions and dosages used in Example 5 and Comparative Example 6 are shown in Table 12.

[0120] Table 12 Material Table of Example 5 and Comparative Example 6

[0121]

[0122]

[0123] The impurities of the compound levodopa and benserazide hydrochloride dual-release preparations prepared from two groups of materials were detected respectively, and the detection results are shown in Table 13.

[0124] Table 13 Detection results of the influence of organic acids on the impurities of the compound levodopa and benserazide hydrochloride dual-release preparations

[0125] Product parameters Test results (%) Impurity content of Example 5 0.5 Impurity content of Comparative Example 6 6.6

[0126] As can be seen from Table 13, the content of impurities in the compound levodopa and benserazide hydrochloride dual-release preparation prepared by wet granulation with tartaric acid solution at the normal prescription amount is only 0.5%, indicating that the compound levodopa and benserazide hydrochloride dual-release preparation is less likely to degrade and the product is stable; while the content of impurities in the compound levodopa and benserazide hydrochloride dual-release preparation prepared without using tartaric acid solution for wet granulation reaches 6.6%, indicating that a large degree of degradation has occurred in the prepared compound levodopa and benserazide hydrochloride dual-release preparation; from this, it can be seen that the use of tartaric acid increases the stability of the prepared compound levodopa and benserazide hydrochloride dual-release preparation, because the pH value of benserazide hydrochloride is 4.0 - 5.0, and benserazide hydrochloride is relatively stable in an acidic environment. Tartaric acid, as an organic acid, is equivalent to a stabilizer, providing an acidic environment for benserazide hydrochloride to make it stable.

[0127] Example 6 and Comparative Example 7 investigated the influence of the type of immediate-release layer binder on the preparation of the compound levodopa and benserazide hydrochloride dual-release preparation. In Example 6, hypromellose E5 was selected as the immediate-release layer binder;

[0128] In Comparative Example 7, povidone K30 was selected as the immediate-release layer binder.

[0129] The preparation methods of the compound levodopa and benserazide hydrochloride dual-release preparations prepared from each group of materials were the same as those in Example 1. The fluidity of the immediate-release layer powder prepared from the two groups of materials was investigated. The material compositions and dosages used in Example 6 and Comparative Example 7 are shown in Table 14.

[0130] Table 14 Material table of Example 6 and Comparative Example 7

[0131]

[0132]

[0133] The fluidity of the powder of the drug-containing immediate-release layer prepared from the two groups of materials was detected respectively, and the detection results are shown in Table 15.

[0134] Table 15 Detection results of the influence of the immediate-release layer binder in Example 6 and Comparative Example 7 on the fluidity of the immediate-release layer powder

[0135] Product Angle of repose ° Test results Immediate-release layer of Example 6 44.08 Qualified Immediate-release layer of Comparative Example 7 47.73 Unqualified

[0136] When the angle of repose of the powder is greater than 45°, the fluidity of the powder is poor. As can be seen from Table 2 and Table 15, the fluidity of the immediate-release layer powder using hypromellose E5 as the binder is qualified; while the fluidity of the immediate-release layer powder using povidone K30 as the binder is poor. It can be seen from this that hypromellose is the preferred immediate-release layer binder.

[0137] Example 7 A compound levodopa and benserazide hydrochloride dual-release preparation

[0138] Example 7 of the present invention provides a compound levodopa and benserazide hydrochloride dual-release preparation, as Figure 4 shown, it can be prepared from any one of Examples 1 to 6. The compound levodopa and benserazide hydrochloride dual-release preparation is composed of a drug-containing immediate-release layer containing levodopa and benserazide hydrochloride and an adjacent drug-containing sustained-release layer containing levodopa and benserazide hydrochloride;

[0139] The drug-containing immediate-release layer further includes an organic acid, a filler, a binder, a disintegrant, and a glidant; the drug-containing sustained-release layer further includes an organic acid, a sustained-release material, a filler, a binder, a glidant, and a lubricant;

[0140] In the compound levodopa and benserazide hydrochloride dual-release preparation, the content of levodopa is 20% to 30%, the content of benserazide hydrochloride is 5% to 10%, the content of the organic acid is 0.2% to 2.0%, the content of the sustained-release material is 25% to 40%, the content of the disintegrant is 0.1% to 2%, the content of the filler is 23% to 40%, the content of the binder is 1.5% to 8%, the content of the glidant is 0.2% to 1%, and the content of the lubricant is 0.2% to 3%;

[0141] Preferably, in the compound levodopa and benserazide hydrochloride dual-release preparation, the content of levodopa is preferably 20 to 25%, the content of benserazide hydrochloride is preferably 5 to 8%, the content of the organic acid is preferably 0.2 to 1%, the content of the sustained-release material is preferably 30 to 40%, the content of the disintegrant is preferably 0.5 to 1%, the content of the filler is preferably 25 to 30%, the content of the binder is preferably 3 to 5%, the content of the glidant is preferably 0.5 to 1%, and the content of the lubricant is preferably 0.5 to 1.5%;

[0142] The organic acid is selected from one or more of the crystals of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, glutamic acid, or aspartic acid, preferably tartaric acid;

[0143] The sustained-release material is selected from one or more of hypromellose, xanthan gum, sodium alginate, and polyethylene oxide, preferably hypromellose, sodium alginate, and polyethylene oxide;

[0144] The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose cross-linked, calcium carboxymethylcellulose, crospovidone and pregelatinized starch, preferably sodium carboxymethylcellulose cross-linked or low-substituted hydroxypropyl cellulose;

[0145] The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch or pregelatinized starch, preferably microcrystalline cellulose;

[0146] The binder is selected from one or more of hypromellose and hydroxypropyl cellulose, preferably hypromellose;

[0147] The glidant is selected from one or more of colloidal silicon dioxide and magnesium stearate, preferably colloidal silicon dioxide;

[0148] The lubricant is selected from one or more of talc, colloidal silicon dioxide, sodium stearyl fumarate or magnesium stearate, preferably magnesium stearate or talc.

[0149] The present invention has been introduced in detail above. Specific examples are used in the present invention to elaborate on the principle and implementation manner of the present invention. The description of the above embodiments is only used to help understand the present invention and its core idea. It should be noted that for those of ordinary skill in the art of this technology, without departing from the principle of the present invention, several improvements and modifications can still be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A preparation method of a compound levodopa and benserazide dual-release preparation, characterized in that, It includes the following steps: S1. Preparation of drug-containing immediate-release layer granules: Weigh appropriate amounts of levodopa, the first group of fillers, disintegrants, binders, and granulate them by wet granulation with an organic acid solution; perform wet screening after wet granulation; dry the wet granules; the moisture content of the dried granules does not exceed 3%, and then perform dry screening; after dry screening, add lubricants and the second group of fillers for premixing, and then add an appropriate amount of benserazide hydrochloride for final mixing to obtain drug-containing immediate-release layer granules; the second group of fillers is microcrystalline cellulose; the binder is hydroxypropyl methylcellulose E5; S2. Preparation of drug-containing sustained-release layer granules: Weigh appropriate amounts of levodopa, the first group of sustained-release materials, fillers, binders, and granulate them by wet granulation with an organic acid solution; perform wet screening after wet granulation; dry the wet granules; the moisture content of the dried granules does not exceed 3%, and then perform dry screening; after dry screening, add lubricants, glidants, and the second group of sustained-release materials for premixing, and then add an appropriate amount of benserazide hydrochloride for final mixing to obtain drug-containing sustained-release layer granules; the first group of sustained-release materials is sodium alginate, hydroxypropyl methylcellulose K100M, and hydroxypropyl methylcellulose K200M; S3. Preparation of compound levodopa and benserazide dual-release tablet cores: Weigh an appropriate amount of drug-containing sustained-release layer granules and place them in the die of a tablet press for pre-pressing; then weigh an appropriate amount of drug-containing immediate-release layer granules and place them in the die of the tablet press to press into compound levodopa and benserazide dual-release tablet cores; S4. Coating: Use a coating solution to coat the compound levodopa and benserazide dual-release tablet cores obtained in step S3 to obtain compound levodopa and benserazide dual-release preparations.

2. The preparation method of the compound levodopa and benserazide dual-release preparation according to claim 1, wherein In the preparation of S1 drug-containing immediate-release layer granules, the content of levodopa weighed is 6% - 10%; the content of the first group of fillers is 4% - 10%; the content of the disintegrant is 0.1% - 2%; the content of the binder is 0.5% - 3%; the content of the organic acid is 0.1% - 0.5%; the content of the lubricant is 0.1% - 1%; the content of the second group of fillers is 2% - 5%; the content of benserazide hydrochloride is 1% - 3%.

3. The preparation method of the compound levodopa and benserazide dual-release preparation according to claim 1, wherein In the preparation of S2 drug-containing sustained-release layer granules, the content of levodopa weighed is 14% - 20%; the content of the first group of sustained-release materials is 22% - 35%; the content of the filler is 17% - 25%; the content of the binder is 1% - 5%; the content of the organic acid is 0.1% - 1.5%; the content of the lubricant is 0.1% - 2%; the content of the glidant is 0.2% - 1%; the content of the second group of sustained-release materials is 3% - 5%; the content of benserazide hydrochloride is 4% - 7%.

4. The preparation method of the compound levodopa and benserazide double-release preparation according to claim 1, wherein, In the preparation of S3 compound levodopa and benserazide dual-release tablet cores, the mass ratio of drug-containing sustained-release layer granules to drug-containing immediate-release layer granules is 3:1 - 4:1; the particle size of benserazide hydrochloride in S1 and S2 does not exceed 0.425 mm.

5. The preparation method of the compound levodopa and benserazide double-release preparation according to claim 1, wherein, In S1 and S2, the organic acid is selected from one or more of the crystals of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, glutamic acid, and aspartic acid; the second group of sustained-release materials is selected from one or more of hydroxypropyl methylcellulose, xanthan gum, sodium alginate, and polyethylene oxide; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl cellulose calcium, crospovidone, and pregelatinized starch; the first group of fillers in S1 and the fillers in S2 are selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, or pregelatinized starch; the binder in S2 is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone; the glidant is selected from one or more of colloidal silica and magnesium stearate; the lubricant is selected from one or more of talc, colloidal silica, sodium stearyl fumarate, or magnesium stearate.

6. The preparation method of the compound levodopa and benserazide dual-release preparation according to claim 1, characterized in that, The first group of fillers in S1 is selected from one or more of lactose, microcrystalline cellulose, mannitol, starch, or pregelatinized starch; The second group of sustained-release materials in S2 is selected from one or two of sodium alginate and polyethylene oxide.

7. The preparation method of the compound levodopa and benserazide double-release preparation according to claim 1, characterized in that, In S4, the coating solution is prepared from a film-forming material, a light-shielding agent, a plasticizer, an anti-adhesive agent, and a coloring agent; the coating weight gain is 2% - 5%.

8. A compound levodopa and benserazide dual-release preparation, characterized in that, Prepared by the preparation method according to any one of claims 1 to 7.

9. The compound levodopa and benserazide dual-release preparation according to claim 8, characterized in that, The drug-containing immediate-release layer comprises an organic acid, a filler, a binder, a disintegrant, and a lubricant; the drug-containing sustained-release layer comprises an organic acid, a sustained-release material, a filler, a binder, a glidant, and a lubricant.

10. The compound levodopa and benserazide dual-release preparation according to claim 9, wherein In the compound levodopa and benserazide hydrochloride dual-release preparation, the content of levodopa is 20% - 30%, the content of benserazide hydrochloride is 5% - 10%, the content of the organic acid is 0.2% - 2.0%, the content of the sustained-release material is 25% - 40%, the content of the disintegrant is 0.1% - 2%, the content of the filler is 23% - 40%, the content of the binder is 1.5% - 8%, the content of the glidant is 0.2% - 1%, and the content of the lubricant is 0.2% - 3%.

Images