Compound breakable sustained-release composition, preparation method thereof, method for improving stability and application of compound breakable sustained-release composition

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a compound breakable sustained-release composition, a preparation method thereof, a method for improving stability and application of the compound breakable sustained-release composition. The invention provides a compound breakable sustained-release composition which comprises an active component, a sustained-release material and a filler in a mass ratio of (0.25-1): 1. According to the invention, the sustained-release material and the filler with specific types and mass fractions are added, the active components are internally added and mixed with the ethanol and the organic acid to serve as the granulation liquid, so that the half tablet and the whole tablet achieve the same sustained-release effect after the composition is broken off, and the tablet is stable and does not crack. The production process is simple and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and in particular to a compound decomposable sustained-release composition and a preparation method thereof, a method for improving stability and an application thereof. Background Art

[0002] Parkinson's disease (PD), also known as "tremor paralysis", usually occurs after the age of 60. Supplementing dopamine in the brain is currently the most commonly used and effective method.

[0003] Dopamine is a neurotransmitter in the brain. The basal ganglia of patients with Parkinson's disease have insufficient dopamine. Levodopa is an intermediate product of dopamine biosynthesis and a dopamine precursor. Dopamine is produced under the action of aromatic L-amino acid decarboxylase. Levodopa can pass through the blood-brain barrier, while dopamine itself cannot, so levodopa is used as a prodrug to increase dopamine levels. However, after administration, levodopa undergoes rapid decarboxylation reactions outside the brain and in brain tissues to produce dopamine, so that most levodopa cannot reach the basal ganglia, and dopamine produced in the periphery often causes adverse reactions. Therefore, it is very necessary to inhibit the decarboxylation reaction of levodopa in tissues outside the brain. This purpose can be achieved by administering levodopa simultaneously with the peripheral decarboxylase inhibitor benserazide. Dopamine is a compound preparation composed of levodopa and benserazide. Dopamine is a compound preparation of levodopa and benserazide in a 4:1 ratio. Clinical trials and therapeutic applications have shown that this ratio has the best therapeutic effect, which is equivalent to the effect of giving a large dose of levodopa alone.

[0004] The market name of dopamine tablets is "Medopar". The specification of Medopar is 250mg (200mg levodopa, 50mg benserazide). It is taken 30 minutes before or 1 hour after meals. The first recommended dose is 0.5 tablets of Medopar each time, three times a day. The daily dose is increased by 0.5 tablets per week until the therapeutic dose suitable for the patient is reached. However, Medopar has no sustained-release effect and needs to be taken frequently every day.

[0005] Prior art Chinese patent CN116531342A discloses a method for preparing a compound dopamine dual-release preparation, which adopts a double-layer tablet design of a drug-containing immediate-release layer and an adjacent drug-containing sustained-release layer to achieve rapid onset of effect and stable control of drug release to maintain long-term effectiveness. However, due to its double-layer tablet design, the preparation process is relatively complicated and the tablet cannot be broken apart for consumption, the dosage cannot be flexibly adjusted, and it is not easy to swallow.

[0006] Prior art Chinese patent CN101242856A discloses a sustained release formulation for delivering one or more pharmaceutically active agents. The formulation comprises cross-linked high-amylose starch and at least one pharmaceutically active agent, and can be optionally subdivided into smaller dosage forms, which have substantially the same release characteristics as the formulation from which the smaller dosage form is derived. However, its stability is poor, and improper prescription ratios can lead to fragmentation. Summary of the invention

[0007] The present invention aims at the technical problems that the dopamine tablets prepared by the prior art preparation method have poor stability, cannot be broken into tablets for use, and after breaking the tablets, the half tablet and the whole tablet cannot achieve the same sustained-release effect. The present invention provides a compound breakable sustained-release composition and a preparation method thereof, a method for improving stability and an application thereof. The present invention adopts a fixed matching ratio of active components, sustained-release materials and fillers, so that after breaking the tablets, the half tablet and the whole tablet achieve the same sustained-release effect. At the same time, the active components are directly mixed with relevant auxiliary materials for granulation, and an organic acid is dissolved in ethanol as a granulation liquid, thereby solving the problem of tablet cracking and ensuring the stability of the tablets.

[0008] The specific technical solutions are as follows:

[0009] In a first aspect, the present invention provides a compound decomposable sustained-release composition, characterized in that it comprises an active component, a sustained-release material and a filler;

[0010] The mass ratio of the sustained-release material to the filler is: 0.25-1:1;

[0011] Preferably, the mass ratio of the sustained-release material to the filler is: 0.3-0.65:1;

[0012] Specifically, the active ingredients include levodopa and benserazide hydrochloride;

[0013] Specifically, the sustained-release material is at least one of hydroxypropyl methylcellulose, xanthan gum, sodium alginate, carbomer and polyethylene oxide;

[0014] Specifically, the filler is at least one of lactose, microcellulose, mannitol and pregelatinized starch;

[0015] Specifically, the compound breakable sustained-release composition further comprises a binder, a glidant, an organic acid and a lubricant;

[0016] Specifically, the binder is at least one of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose;

[0017] Specifically, the glidant is at least one of colloidal silicon dioxide and talc;

[0018] Specifically, the organic acid is at least one of crystals of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, glutamic acid and aspartic acid;

[0019] Specifically, the lubricant is at least one of talc, hydrogenated vegetable oil, sodium stearyl fumarate and magnesium stearate;

[0020] Preferably, the filler is microcrystalline cellulose or mannitol;

[0021] Preferably, the filler is microcrystalline cellulose PH101, mannitol 160C;

[0022] Preferably, the binder is hydroxypropyl cellulose;

[0023] Preferably, the sustained-release material is hypromellose;

[0024] Preferably, the sustained-release material is hypromellose K100M;

[0025] Preferably, the organic acid is tartaric acid;

[0026] Preferably, the glidant is colloidal silicon dioxide;

[0027] Preferably, the lubricant is magnesium stearate.

[0028] Specifically, the compound decomposable sustained-release composition comprises the following components in percentage by mass: 15-75% of levodopa, 5-30% of benserazide hydrochloride, 5-50% of sustained-release material, 10-60% of filler, 1-20% of binder, 0.2-5% of glidant, 0.1-8% of organic acid and 0.2-5% of lubricant;

[0029] Preferably, the compound decomposable sustained-release composition comprises the following components by mass: 25-55% levodopa, 10-20% benserazide hydrochloride, 5-15% sustained-release material, 10-40% filler, 1-10% binder, 0.2-2% by mass of glidant, 0.5-5% organic acid and 0.2-2% lubricant.

[0030] In a second aspect, the present invention provides a method for preparing a composite decomposable sustained-release composition, comprising the following steps:

[0031] S1, mixing the active ingredient, filler and sustained-release material, adding granulation liquid for granulation, and obtaining wet granules;

[0032] S2, granulating and drying the wet granules obtained in step S1 to obtain dry granules;

[0033] or

[0034] (1) mixing the active ingredient and the filler, adding a granulating liquid for granulation to obtain wet granules;

[0035] (2) The wet granules obtained in step (1) are granulated, dried, and mixed with a sustained-release material to obtain premixed granules.

[0036] Specifically, the granulation liquid is a mixture of organic acid and ethanol;

[0037] Specifically, the ethanol is anhydrous ethanol;

[0038] Specifically, the content of ethanol is added until the organic acid is dissolved;

[0039] Specifically, the preparation method comprises the following steps:

[0040] S1, mixing the active ingredient, filler, sustained-release material and binder, adding granulating liquid for granulation to obtain wet granules;

[0041] S2, granulating and drying the wet granules obtained in step S1 to obtain dry granules;

[0042] S3, premixing the glidant with the dry granules obtained in step S2 to obtain premixed granules;

[0043] or

[0044] (1) mixing the active ingredient, filler and binder, adding granulating liquid for granulation to obtain wet granules;

[0045] (2) granulating and drying the wet granules obtained in step (1) and mixing them with a sustained-release material and a glidant to obtain premixed granules;

[0046] Specifically, the steps further include: total mixing and tableting;

[0047] Specifically, the total mixing is mixing the lubricant with the premixed particles.

[0048] In a third aspect, the present invention provides a formulation composition comprising a compound decomposable sustained-release composition and a pharmaceutically acceptable excipient.

[0049] Specifically, the preparation composition can be broken apart and taken;

[0050] In a fourth aspect, the present invention provides a method for improving the stability of a compound decomposable sustained-release composition.

[0051] Specifically, the compound breakable sustained-release composition comprises an active component, a sustained-release material, and a filler;

[0052] Specifically, the steps include:

[0053] S1, mixing the active ingredient, filler and sustained-release material, and granulating with a granulating liquid to obtain wet granules;

[0054] S2, granulating and drying the wet granules obtained in step S1 to obtain dry granules;

[0055] or

[0056] (1) mixing the active ingredient and the filler, and granulating the mixture using a granulating liquid to obtain wet granules;

[0057] (2) granulating and drying the wet granules obtained in step (1) and mixing them with a sustained-release material to obtain premixed granules;

[0058] Specifically, the active ingredients include levodopa and benserazide hydrochloride;

[0059] Specifically, the filler is at least one of lactose, microcellulose, mannitol and pregelatinized starch;

[0060] Specifically, the sustained-release material is at least one of hydroxypropyl methylcellulose, xanthan gum, sodium alginate, carbomer and polyethylene oxide;

[0061] Specifically, the granulation liquid is a mixture of organic acid and ethanol;

[0062] Specifically, the content of ethanol is added until the organic acid is dissolved;

[0063] Specifically, the ethanol is anhydrous ethanol;

[0064] Specifically, the organic acid is at least one of crystals of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, glutamic acid and aspartic acid.

[0065] In a fifth aspect, the present invention provides a use of a compound breakable sustained-release composition in the preparation of a drug for treating Parkinson's disease.

[0066] The "content" of each component in the first aspect and the second aspect refers to the percentage of the mass of each component to the total mass of the oral compound dopamine sustained-release composition.

[0067] Compared with the prior art, the present invention has the following beneficial effects:

[0068] (1) The present invention provides a compound breakable sustained-release composition, which combines an active component and a specific sustained-release material and its content with a specific filler and its content, so that after breaking the tablet, the half tablet and the whole tablet have the same sustained-release effect;

[0069] (2) The present invention provides a method for improving the stability of a compound decomposable sustained-release composition, wherein the active substance is directly mixed with relevant auxiliary materials for granulation, and an organic acid is dissolved in ethanol as a granulation liquid, thereby solving the tablet cracking problem and ensuring the stability of the tablet.

[0070] (3) The preparation process provided by the present invention is simple, has good reproducibility, and is easy to industrialize and mass produce. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] The present invention will be further described in detail below in conjunction with the accompanying drawings and preferred embodiments, but those skilled in the art will appreciate that these drawings are drawn only for the purpose of explaining the preferred embodiments and therefore should not be used as a limitation on the scope of the present invention. In addition, unless otherwise specified, the drawings are only schematically representing the composition or structure of the described objects and may contain exaggerated displays, and the drawings are not necessarily drawn to scale.

[0072] Figure 1 The dissolution rates of the whole tablet and half tablet of levodopa and benserazide hydrochloride in Example 1;

[0073] Figure 2 The dissolution rates of the whole tablet and half tablet of levodopa and benserazide hydrochloride in Example 2;

[0074] Figure 3 The dissolution rates of the whole tablet and half tablet of levodopa and benserazide hydrochloride in Example 3;

[0075] Figure 4 The dissolution rates of the whole tablet and half tablet of levodopa and benserazide hydrochloride in Comparative Example 3;

[0076] Figure 5 The dissolution rates of the whole tablet and half tablet of levodopa and benserazide hydrochloride in Example 4;

[0077] Figure 6 The dissolution rates of the whole tablet and half tablet of levodopa and benserazide hydrochloride in Example 5;

[0078] Figure 7 The dissolution rates of the whole tablet and half tablet of levodopa and benserazide hydrochloride in Comparative Example 5;

[0079] Figure 8 The dissolution rates of the whole tablet and half tablet of levodopa and benserazide hydrochloride in Comparative Example 6; DETAILED DESCRIPTION

[0080] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0081] The technical details of the present invention are described in detail by the following examples. It should be noted that the examples are only used to further illustrate the technical features of the present invention, rather than to limit the protection scope of the present invention.

[0082] Unless otherwise specified, all commodities or reagents in the present invention were purchased through market channels.

[0083] The content of ethanol in the present invention is added until the organic acid is dissolved, and the specific ethanol content can be increased or decreased within a conventional selection range by those skilled in the art according to the granulation conditions.

[0084] 1. Examples and Comparative Examples

[0085] Example 1

[0086] The raw and auxiliary materials are shown in Table 1.

[0087] Table 1 Example 1 Material List

[0088]

[0089] Embodiment 1 The specific preparation process is as follows:

[0090] S1. Pass all raw and auxiliary materials through a 40-mesh sieve, mix levodopa, benserazide hydrochloride, filler, binder and sustained-release material as internal materials according to the specified proportions, add anhydrous ethanol to the organic acid until the organic acid is dissolved as a granulation liquid and perform wet granulation with the internal materials;

[0091] S2, wet granulation followed by wet granulation, the obtained wet granulation particle size is 2.0 mm, fluidized bed drying at 40°C, and dry granulation after drying, the particle size is 1.5 mm;

[0092] S3, passing colloidal silicon dioxide and magnesium stearate through a 40-mesh sieve, weighing a prescribed amount of colloidal silicon dioxide and premixing with the dry whole granules, and then mixing with the prescribed amount of magnesium stearate after premixing to obtain the composition;

[0093] S4. Take the prescribed amount of the composition granules and place them in the die of a tablet press to press them into tablets.

[0094] Example 2

[0095] The formula is the same as that of Example 1, except that the sustained-release material is added in the preparation process.

[0096] Embodiment 2 The specific preparation process is as follows:

[0097] S1. Pass all raw and auxiliary materials through a 40-mesh sieve, mix levodopa, benserazide hydrochloride, filler and binder according to the specified proportions as internal materials, add anhydrous ethanol to the organic acid until the organic acid is dissolved as a granulation liquid and perform wet granulation with the internal materials;

[0098] S2, wet granulation followed by wet granulation, the obtained wet granulation particle size is 2.0 mm, fluidized bed drying at 40°C, and dry granulation after drying, the particle size is 1.5 mm;

[0099] S3. Pass colloidal silicon dioxide, hypromellose K100M and magnesium stearate through a 40-mesh sieve respectively, weigh the prescribed amount of colloidal silicon dioxide and hypromellose K100M and premix them with the dry whole granules, and then mix them with the prescribed amount of magnesium stearate after premixing to obtain the composition.

[0100] S4. Take the prescribed amount of the composition granules and place them in the die of a tablet press to press them into tablets.

[0101] Example 3

[0102] The difference from Example 1 is that the sustained-release material is replaced by sodium alginate. The preparation process is the same as that of Example 1. The raw and auxiliary materials are shown in Table 2.

[0103] Table 2 Material list of Example 3

[0104]

[0105] Example 4

[0106] The raw and auxiliary materials are shown in Table 3, and the preparation method is the same as Example 2.

[0107] Table 3 Material list of Example 4

[0108]

[0109]

[0110] Example 5

[0111] The raw and auxiliary materials are shown in Table 4, and the preparation method is the same as Example 2.

[0112] Table 4 Example 5 Material List

[0113]

[0114] Comparative Example 1

[0115] The difference from Example 1 is that the mass ratio of sustained-release material to filler is 0.2:1. The preparation process is the same as that of Example 1. The raw and auxiliary materials are shown in Table 5.

[0116] Table 5 Comparative Example 1 Material List

[0117]

[0118] Comparative Example 2

[0119] The difference from Example 1 is that the mass ratio of sustained-release material to filler is 1.16:1. The preparation process is the same as that of Example 1. The raw and auxiliary materials are shown in Table 6.

[0120] Table 6 Comparative Example 2 Material List

[0121]

[0122] Comparative Example 3

[0123] The difference from Example 2 is that the type of sustained-release material is replaced by ethyl cellulose, and the preparation process is the same as that of Example 2.

[0124] Comparative Example 4

[0125] The difference from Example 4 is that the filler type is replaced by anhydrous calcium hydrogen phosphate, the preparation process is the same as that of Example 2, and the raw and auxiliary materials are shown in Table 7.

[0126] Table 7 Comparative Example 4 Material List

[0127]

[0128] Comparative Example 5

[0129] The preparation process is the same as that of Example 2, the mass fraction of the sustained-release material is 52.5%, and the raw and auxiliary materials are shown in Table 8.

[0130] Table 8 Comparative Example 5 Material List

[0131]

[0132] Comparative Example 6

[0133] The preparation process is the same as that of Example 2, the mass fraction of the sustained-release material is 3.75%, and the raw and auxiliary materials are shown in Table 9.

[0134] Table 9 Comparative Example 6 Material List

[0135]

[0136] Comparative Example 7

[0137] The preparation process is the same as that of Example 2, the mass fraction of the filler is 9.5%, and the raw and auxiliary materials are shown in Table 10.

[0138] Table 10 Comparative Example 7 Material List

[0139]

[0140]

[0141] Comparative Example 8

[0142] The preparation process is the same as that of Example 2, the mass fraction of the filler is 52.5%, and the raw and auxiliary materials are shown in Table 11.

[0143] Table 11 Comparative Example 8 Material List

[0144]

[0145] Comparative Example 9

[0146] The difference of Example 1 is that ethanol is replaced by water. The preparation method is the same as that of Example 1. The raw and auxiliary materials are shown in Table 12.

[0147] Table 12 Comparative Example 9 Material List

[0148]

[0149] Comparative Example 10

[0150] The difference from Example 1 is that benserazide hydrochloride is added externally. The preparation method is the same as that of Example 1. The raw and auxiliary materials are shown in Table 13.

[0151] Table 13 Comparative Example 10 Material List

[0152]

[0153] The specific preparation process of Comparative Example 10 is as follows:

[0154] S1. Pass all raw and auxiliary materials through a 40-mesh sieve, mix levodopa, microcrystalline cellulose, lactose, hydroxypropyl cellulose, and hypromellose K100M as internal materials according to the specified proportions, add anhydrous ethanol to the organic acid until the organic acid is dissolved, and use it as a granulation liquid to perform wet granulation with the internal materials;

[0155] S2, wet granulation followed by wet granulation, the obtained wet granulation particle size is 2.0 mm, fluidized bed drying at 40°C, and dry granulation after drying, the particle size is 1.5 mm;

[0156] S3, respectively passing colloidal silicon dioxide, benserazide hydrochloride, and magnesium stearate through a 40-mesh sieve, weighing a prescribed amount of colloidal silicon dioxide and benserazide hydrochloride and premixing them with the dry whole granules, and then mixing them with the prescribed amount of magnesium stearate after premixing to obtain the composition;

[0157] S4. Take the prescribed amount of the composition granules and place them in the die of a tablet press to press them into tablets.

[0158] 2. Tablet friability test

[0159] According to the 2020 edition of the Chinese Pharmacopoeia Tablet Friability Test Method (General Rule 0923), the friability of the compound breakable sustained-release composition is tested as follows:

[0160] For tablets weighing 0.65g or less, take a number of tablets so that the total weight is about 6.5g; for tablets weighing more than 0.65g, take 10 tablets. Use a hair dryer to blow away the powder that falls off the tablets, weigh them accurately, place them in the cylinder of the friability tester, and rotate them 100 times. Take them out, remove the powder in the same way, weigh them accurately, and the weight loss shall not exceed 1%, and no broken, cracked, or crushed tablets shall be detected. This test is generally performed only once. If the weight loss exceeds 1%, it should be repeated twice, and the average weight loss of the three times shall not exceed 1%, and no broken, cracked, or crushed tablets shall be detected.

[0161] The friability of the composite breakable sustained-release composition prepared in the present invention was evaluated according to the above method. The results are shown in Table 14.

[0162] Table 14 Tablet stability of Examples 1-5 and Comparative Examples 1-10

[0163] Whether it is sticky Whether it is a fragment Tablet friability (%) Example 1 no no 0.03 Example 2 no no 0.28 Example 3 no no 0.19 Example 4 no no 0.12 Example 5 no no 0.22 Comparative Example 1 no yes 1.22 Comparative Example 2 no yes 1.13 Comparative Example 3 no no 0.42 Comparative Example 4 Slight stickiness no 0.42 Comparative Example 5 no yes 1.23 Comparative Example 6 no yes 1.45 Comparative Example 7 Slight stickiness yes 0.89 Comparative Example 8 Slight stickiness yes 0.72 Comparative Example 9 yes / / Comparative Example 10 yes / /

[0164] As in Examples 1-5, when the mass ratio of the sustained-release material to the filler is 0.25-1:1, the preparation has good stability, does not stick to the punch, does not crack, and has low tablet friability. By comparing Comparative Examples 1 and 2 with Example 1, when the mass ratio of the sustained-release material to the filler is 0.2 (Comparative Example 1) and 1.16 (Comparative Example 2), the tablet friability is greater than 1%, and cracks are easily generated, which does not meet the requirements.

[0165] As in Examples 1-5, the fillers of lactose, microcellulose, mannitol or pregelatinized starch can make the tablets stable, not cracked or sticky, and have a friability of less than 1%. When anhydrous calcium hydrogen phosphate is selected as the filler (Comparative Example 4), the tablets will have a slight sticking phenomenon.

[0166] Compared with Example 5, the mass fractions of the sustained-release material in Comparative Examples 5-6 are different. Experiments show that when the mass fraction of the sustained-release material is too low (3.75%) or too high (52.5%), the tablet friability is greater than 1%, and tablet cracking is likely to occur.

[0167] Compared with Example 4, Comparative Examples 7-8 have different filler mass fractions. Experiments have found that when the filler mass fraction is too low (9.5%) or too high (52.5%), sticking is likely to occur, which is not conducive to production expansion.

[0168] The difference between Comparative Example 9 and Example 1 is that the granulation liquid of Example 1 is ethanol, and the granulation liquid of Comparative Example 9 is aqueous solution. Experiments have found that the tablets of Comparative Example 9 are prone to sticking during the pressing process, which is not conducive to large-scale production.

[0169] The difference between Comparative Example 10 and Example 1 is that, in Example 1, benserazide hydrochloride is added internally, while in Comparative Example 10, benserazide hydrochloride is added externally. Experiments have shown that after benserazide hydrochloride is added externally, sticking and punching occur during the pressing process, which is not conducive to large-scale production.

[0170] 3. Dissolution Test

[0171] Chinese Pharmacopoeia 2015 Edition Part IV General Chapter 0931 Method 2, paddle method 75rpm, 37℃, 1000mL pH1.2 medium, with sinker.

[0172] pH 1.2 medium preparation: Measure 7.65 mL of hydrochloric acid, add water to 1000 mL, mix well, and degas by ultrasonication.

[0173] The dissolution rates of the whole tablet and half tablet of the compound breakable sustained-release composition prepared in the present invention were measured according to the above method, and the similarity factor f2 was calculated. An f2 value greater than or equal to 50 indicates that the dissolution behaviors of the two preparations are similar. The results are shown in Table 15.

[0174] Table 15 Dissolution and similarity factors of whole and half tablets of Examples 1-5 and Comparative Examples 3, 5 and 6

[0175]

[0176]

[0177] As in Examples 1-5, when the sustained-release material is hydroxypropyl methylcellulose, xanthan gum, sodium alginate, and carbomer, the tablet stability is good. At the same time, dissolution experiments are performed on Examples 1-5, and the f2 values ​​of the two active components are calculated according to the solubility. The f2 values ​​of Examples 1-5 are all ≥50, indicating that the whole tablet and the half tablet have comparable sustained-release effects. Figure 1-Figure 3 and Figure 5-Figure 6 When ethyl cellulose was selected as the sustained-release material (Comparative Example 3), the f2 values ​​of the two active components were both <50, indicating that the dissolution of the whole tablet and the half tablet had no similarity and no equivalent sustained-release effect.

[0178] Compared with Example 5, the mass fraction of the sustained-release material in Comparative Examples 5-6 is different. The experiment found that when the mass fraction of the sustained-release material is too low (3.75%) or too high (52.5%), the dissolution similarity of the whole and half tablets of the breakable sustained-release tablets is quite different. Figure 6-Figure 8 .

[0179] The present invention is described in detail above. The present invention uses specific examples to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the present invention and its core ideas. It should be pointed out that for ordinary technicians in this technical field, without departing from the principles of the present invention, the present invention can also be improved and modified in a number of ways, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A compound breakable sustained-release composition, characterized in that: Includes active ingredients, sustained-release materials and fillers; The mass ratio of the sustained-release material to the filler is 0.25-1:

1.

2. The compound decomposable sustained-release composition according to claim 1, characterized in that: The mass ratio of sustained-release material to filler is: 0.3-0.65:1; The active ingredients include levodopa and benserazide hydrochloride; and / or The sustained-release material is at least one of hydroxypropyl methylcellulose, xanthan gum, sodium alginate, carbomer and polyethylene oxide; and / or The filler is at least one of lactose, microcellulose, mannitol and pregelatinized starch.

3. The compound decomposable sustained-release composition according to claim 1, characterized in that: Also included are binders, glidants, organic acids, and lubricants; The binder is at least one of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose; and / or The glidant is at least one of colloidal silicon dioxide and talc; and / or The organic acid is at least one of crystals of tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, glutamic acid and aspartic acid; and / or The lubricant is at least one of talc, hydrogenated vegetable oil, sodium stearyl fumarate and magnesium stearate.

4. The compound decomposable sustained-release composition according to claim 3, characterized in that: The invention comprises the following components in percentage by weight: 15-75% of levodopa, 5-30% of benserazide hydrochloride, 5-50% of sustained-release material, 10-60% of filler, 1-20% of binder, 0.2-5% of glidant, 0.1-8% of organic acid and 0.2-5% of lubricant; Furthermore, the invention comprises the following components in percentage by mass: 25-55% of levodopa, 10-20% of benserazide hydrochloride, 5-15% of sustained-release material, 10-40% of filler, 1-10% of binder, 0.2-2% of glidant, 0.5-5% of organic acid and 0.2-2% of lubricant.

5. A method for preparing the composite sustained-release composition according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1, mixing the active ingredient, filler and sustained-release material, adding granulation liquid for granulation, and obtaining wet granules; S2, granulating and drying the wet granules obtained in step S1 to obtain dry granules; or (1) mixing the active ingredient and the filler, adding a granulating liquid for granulation to obtain wet granules; (2) The wet granules obtained in step (1) are granulated, dried, and mixed with a sustained-release material to obtain premixed granules.

6. The preparation method according to claim 5, characterized in that: The following steps are involved: S1, mixing the active ingredient, filler, sustained-release material and binder, and granulating with a granulating liquid to obtain wet granules; S2, granulating and drying the wet granules obtained in step S1 to obtain dry granules; S3, premixing the glidant with the dry granules obtained in step S2 to obtain premixed granules; or (1) mixing the active ingredient, filler and binder, and granulating with a granulating liquid to obtain wet granules; (2) granulating and drying the wet granules obtained in step (1) and mixing them with a sustained-release material and a glidant to obtain premixed granules; The preparation method further comprises: total mixing and tableting; The total mixing is mixing the lubricant with the premixed particles.

7. The preparation method according to claim 6, characterized in that: The granulation liquid is a mixture of organic acid and ethanol; The ethanol is anhydrous ethanol; The content of the ethanol is such that the ethanol is added until the organic acid is dissolved.

8. A method for improving the stability of a compound decomposable sustained-release composition, characterized in that: The compound decomposable sustained-release composition comprises an active component, a sustained-release material and a filler; The method comprises the following steps: S1, mixing the active ingredient, filler and sustained-release material, adding granulation liquid for granulation, and obtaining wet granules; S2, granulating and drying the wet granules obtained in step S1 to obtain dry granules; or (1) mixing the active ingredient and the filler, adding a granulating liquid for granulation to obtain wet granules; (2) granulating and drying the wet granules obtained in step (1) and mixing them with a sustained-release material to obtain premixed granules; The active ingredients include levodopa and benserazide hydrochloride; The filler is at least one of lactose, microcellulose, mannitol and pregelatinized starch; The sustained-release material is at least one of hydroxypropyl methylcellulose, xanthan gum, sodium alginate, carbomer and polyethylene oxide; The granulation liquid is a mixture of organic acid and ethanol; The content of the ethanol is such that the ethanol is added until the organic acid is dissolved.

9. Use of the compound decomposable sustained-release composition according to any one of claims 1 to 4 or the compound decomposable sustained-release composition prepared by the preparation method according to any one of claims 5 to 7 in preparing a drug for treating Parkinson's disease.

10. A preparation composition, characterized in that: It comprises the compound decomposable sustained-release composition according to any one of claims 1 to 4 or the compound decomposable sustained-release composition prepared by the preparation method according to any one of claims 5 to 7 and pharmaceutically acceptable excipients; The preparation composition can be broken into pieces for oral administration.

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