Multi-system drug release system for Parkinson's disease treatment and preparation method thereof

Abstract

The invention discloses a multi-system drug release system for Parkinson's disease treatment, which is a capsule prepared from the following drug release systems and auxiliary materials in percentage by weight: 58.0 to 64.1 percent of an entacapone drug release system, 28.5 to 31.5 percent of a levodopa drug release system, 7.6 to 8.4 percent of a carbidopa drug release system and 0.5 to 1.5 percent of talcum powder, the drug-loaded pellet of the entacapone drug release system comprises a first pellet core, an isolation layer and an enteric layer which are sequentially arranged from inside to outside, and the drug-loaded pellet of the levodopa drug release system comprises a second pellet core and a first modification layer which are sequentially arranged from inside to outside, the drug-loaded pellet of the carbidopa drug release system comprises a third pellet core and a second modification layer which are sequentially arranged from inside to outside. The multi-system drug release system can realize independent and long-term slow release of three different active components without mutual interference. According to the method, a multi-system drug release system can be prepared with high loading capacity, and the problem of large dosage of drugs is effectively solved.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a multi-system drug release system for treating Parkinson's disease and a preparation method thereof. Background Art

[0002] Parkinson's disease is a common degenerative disease of the nervous system in middle-aged and elderly people. It is mainly characterized by the pathological changes of progressive degeneration of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies, biochemical changes of dopamine transmitter reduction in the striatum, imbalance of dopamine and acetylcholine transmitters, motor symptoms of tremor, muscle rigidity, bradykinesia, postural balance disorder, and clinical manifestations of non-motor symptoms such as sleep disorders, olfactory disorders, autonomic dysfunction, cognitive and mental disorders. As the disease progresses, the motor and non-motor symptoms of Parkinson's disease will gradually worsen, which will not only impair the patient's daily activities, but also bring huge social and medical burdens.

[0003] Parkinson's disease treatment methods and means include drug therapy, surgical treatment, botulinum toxin treatment, exercise therapy, psychological intervention, care and nursing, etc. Drug therapy is the first choice and the main treatment method in the whole treatment process. Surgery is an effective supplementary means when drug treatment is not effective. Botulinum toxin injection is an effective method for treating local spasms and dystonia. Exercise and rehabilitation therapy, psychological intervention and care and nursing are applicable to the whole treatment of Parkinson's disease.

[0004] At present, there are many drugs that can effectively improve Parkinson's disease in clinical practice, which are mainly divided into 6 categories, including:

[0005] 1. DDC inhibitors: Levodopa is the standard treatment for Parkinson's disease and the most effective symptomatic drug for Parkinson's disease. However, in most patients, with the progression of the disease and long-term or high-dose use of levodopa, motor complications will occur, including symptom fluctuations and dyskinesia. At this time, the combination of levodopa and carbidopa can be used as the first choice. The combination of immediate-release preparations has the characteristics of rapid onset, while the sustained-release tablets have a relatively long maintenance time, but slow onset and low bioavailability. When using, especially when switching between two different dosage forms, it is necessary to pay attention.

[0006] 2. Dopamine receptor agonists: including ergot DAs and non-ergot DAs. Ergots are no longer recommended for clinical use because they may cause serious adverse reactions to valvular disease. Non-ergots are recommended as the first choice for patients with early-onset disease in the early stages of the disease, including pramipexole, ropinirole, piribedil, rotigotine and apomorphine.

[0007] 3. MAO-BI: including the first-generation MAO-BI selegiline and the second-generation MAO-BI rasagiline, as well as dual-channel blockers safinamide and zonisamide. They can improve the motor symptoms of patients with Parkinson's disease.

[0008] 4. Catechol-O-methyltransferase (COMT) inhibitors: mainly entacapone, opicapone and entacapone bidopa tablets combined with compound levodopa (entacapone / levodopa / carbidopa compound preparation). Entacapone bidopa tablets are the first choice for treatment in the early stage of the disease to improve symptoms, and adding COMTI treatment in the middle and late stages of the disease can further improve symptoms.

[0009] 5. Anticholinergics and amantadine drugs.

[0010] 6. Entacapone / levodopa / carbidopa combination is a drug combination that is currently widely used in clinical practice and is also the preferred drug combination for the treatment of Parkinson's disease.

[0011] Entacapone is a new generation of COMT (catechol-O-methyltransferase) inhibitors. It is a highly selective, low-toxic, and highly effective COMT inhibitor that is still active when taken orally. It is used to treat Parkinson's disease and must be used simultaneously with levodopa preparations. It can effectively inhibit COMT enzymes to reduce the metabolism of levodopa to 3-oxo-methyldopa (3-OMD), increase the bioavailability of levodopa in the central nervous system, and increase the total amount of levodopa available in the brain, reducing its dosage and the number of medications, and improving motor fluctuations caused by long-term treatment with levodopa. Patients tolerate it well, but the duration of action is short (2h). The chemical name is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-acrylamide, yellow powder, molecular formula is C14H15N3O5, and the structural formula is as follows:

[0012]

[0013] Levodopa, chemical name 3-(3,4-dihydroxyphenyl)-L-alanine, is a DDC inhibitor with a chemical formula of C9H11NO4. It is a dopamine prodrug and has no pharmacological activity. It enters the central nervous system through the blood-brain barrier and is converted into DA by dopa decarboxylase to exert its pharmacological effects. The structural formula is as follows:

[0014]

[0015] Carbidopa is a peripheral L-aromatic amino acid decarboxylase inhibitor. It cannot pass through the blood-brain barrier and enter the brain. Therefore, when used in combination with levodopa, it can inhibit the conversion of peripheral levodopa into dopamine, reduce the generation of peripheral DA, reduce side effects, and increase the amount of levodopa entering the central nervous system, increasing the content of levodopa in the circulating blood by 5 to 10 times. Therefore, more levodopa can reach the substantia nigra-striatum to play a role, thereby improving the efficacy of levodopa and reducing the adverse reactions of levodopa in the periphery. The chemical name is (S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methyl-propionic acid, and the chemical formula is C10H14N2O4. It is mainly used as a decarboxylase inhibitor and is used together with levodopa to treat Parkinson's disease.

[0016]

[0017] In our research on Parkinson's disease and corresponding drug treatment, we unexpectedly discovered external factors that affect the full efficacy and safety of entacapone, levodopa, and carbidopa in the body. The presence of these factors will weaken the therapeutic effect of the drugs and seriously damage the cost-effectiveness of the drugs. The relevant adverse external factors will be fully explained below.

[0018] 1) One of the unfavorable external factors

[0019] Entacapone contains a cyano group (-C≡N) in its structure, which is easily hydrolyzed under acidic conditions to produce carboxylic acids and other organic impurities. The degradation mechanism is as follows:

[0020]

[0021] Related studies have shown that if the drug is destroyed in an acidic environment for 0.5 hours or more, more than 8% of entacapone will be degraded. After the drug enters the gastric acid environment through the digestive tract, it will stay and be released in the acidic environment, thus causing the degradation of entacapone in the body, which will not only reduce the absorption and bioavailability of the drug, but also bring safety risks. This point needs to be studied and solved.

[0022] 2) The second unfavorable external factor

[0023] The disclosed entacapone / levodopa / carbidopa compound preparations are mainly entacapone / levodopa / carbidopa compound regular release preparations, and a combination of entacapone regular release and levodopa / carbidopa compound sustained release preparations. The first drug combination has a short action time in the body and cannot achieve long-term drug release. Patients need to increase the frequency of medication, which is not conducive to the stability of blood drug concentration in the body, thereby reducing the effect of the drug in the body; the second drug combination can achieve long-term drug release of levodopa and carbidopa, but entacapone does not have a long-term sustained release, and cannot maintain a sustained and effective blood drug concentration, resulting in a large difference from the in vivo pharmacokinetic curve of levodopa, and the effect of inhibiting the O-methylation of levodopa is not sustained enough, and it cannot play a good role in improving the bioavailability of levodopa. CN102170869A discloses a preparation combination in which entacapone is a regular release characteristic and levodopa and carbidopa are a sustained release characteristic in its public documents, but does not solve the above-mentioned problems.

[0024] 3) The third unfavorable external factor

[0025] In the disclosed entacapone / levodopa / carbidopa composite sustained-release preparations, entacapone, levodopa and carbidopa are prepared using the same sustained-release system, or entacapone uses one sustained-release system, and levodopa and carbidopa use one sustained-release system, and the release cannot be precisely regulated. As auxiliary drugs for improving the bioavailability of levodopa, entacapone and carbidopa have different solubility and permeability, which will lead to differences in drug absorption in the body and concentration differences at the target site, and cannot maximize the bioavailability of levodopa in the body, which is also a defect in product design. CN102170870A discloses a combination of sustained-release preparations of three active ingredients in its public documents, but does not solve the above-mentioned problems.

[0026] In view of the above-mentioned unfavorable external factors, the present invention provides a multi-system drug release system for treating Parkinson's disease and a preparation method thereof. Summary of the invention

[0027] The technical problem to be solved by the present invention is to provide a multi-system drug release system for Parkinson's disease treatment and a preparation method thereof, in view of the deficiencies of the prior art, to improve the stability and bioavailability of drugs and to increase the cost-effectiveness of drugs. The multi-system drug release system can realize the independent release of three different active ingredients, namely, entacapone, levodopa and carbidopa, without interfering with each other, and also realizes the purpose of long-term and slow release of the three active ingredients, thereby better exerting the clinical therapeutic effect of Parkinson's disease and meeting the release requirements for treatment and maximum cost-effectiveness.

[0028] The technical solution adopted by the present invention to solve the above technical problems is: a multi-system drug release system for Parkinson's disease treatment, wherein the multi-system drug release system is a capsule prepared from drug release systems and excipients in the following weight percentage ratios: 58.0-64.1% of entacapone drug release system, 28.5-31.5% of levodopa drug release system, 7.6-8.4% of carbidopa drug release system and 0.5-1.5% of talc, wherein the entacapone drug release system, the levodopa drug release system and the carbidopa drug release system are The drug release system is composed of drug-loaded micropellets. The drug-loaded micropellets of the entacapone drug release system include a first core, an isolation layer and an enteric layer arranged in sequence from the inside to the outside, and the first core contains the entacapone raw material. The drug-loaded micropellets of the levodopa drug release system include a second core and a first modified layer arranged in sequence from the inside to the outside, and the second core contains the levodopa raw material. The drug-loaded micropellets of the carbidopa drug release system include a third core and a second modified layer arranged in sequence from the inside to the outside, and the third core contains the carbidopa raw material.

[0029] The multi-system drug release system of the present invention includes three independent drug release systems, with entacapone drug release system, levodopa drug release system and carbidopa drug release system in the form of drug-loaded pellets as the main components, and the drug-loaded pellets are prepared into capsules by making the drug into drug-loaded pellets with different drug loading and release characteristics, and filling the drug-loaded pellets with talcum powder. Among them, the entacapone drug release system is an enteric-coated sustained-release double-release pellet, which can effectively improve the stability and bioavailability of entacapone in the body, solve the problem that entacapone is unstable in gastric acid and cannot be released for a long time; the levodopa drug release system and the carbidopa drug release system are both sustained-release pellets, which can improve the uniformity and independence of levodopa and carbidopa release. The multi-system drug release system of the present invention can realize the independent release of three different active ingredients of entacapone, levodopa and carbidopa without interfering with each other, and also realizes the purpose of long-term slow release of the three active ingredients, so as to better play the clinical therapeutic effect of Parkinson's disease and meet the release requirements for treatment and maximum cost-effectiveness.

[0030] The drug-loaded micropellets of the entacapone drug delivery system include a first core, an isolation layer and an enteric layer. The isolation effect of the enteric layer reduces the contact between entacapone and gastric acid, so that it is no longer affected by the acidic solution and degraded. The independent entacapone drug delivery system can release entacapone at the designed release rate, better play its role in assisting levodopa to produce better pharmacological effects, and improve bioavailability.

[0031] The drug-loaded micro-pellets of the levodopa drug delivery system include a second pellet core and a first modified layer. The independent levodopa drug delivery system can release levodopa at a designed release rate, so that it can be released for a long time in the body, maintain the blood drug concentration in the therapeutic window, and thus play a long-term role.

[0032] The drug-loaded micropellets of the carbidopa drug delivery system include a third pellet core and a second modified layer. The independent carbidopa drug delivery system can release carbidopa at a designed release rate, better play its role in assisting levodopa to produce better pharmacological effects, and improve bioavailability.

[0033] The multi-system drug release system of the present invention is a drug release system that is convenient for patients to administer drugs, and can be administered in a variety of ways to improve the compliance of patients with drug use.

[0034] Preferably, the weight percentage of each component of the drug-loaded pellets of the entacapone drug delivery system is as follows: 100% of the first pellet core, 6-10% of the isolation layer and 10-23% of the enteric layer, wherein the weight percentage of the first pellet core is: 40-60% of the entacapone raw material, 5-34.5% of the first filler, 20-26% of the first sustained-release skeleton material, 5-8% of the first adhesive and 0.5-1.5% of the first lubricant, the weight percentage of the isolation layer is: 75-85% of the first film-forming material and 15-25% of the first plasticizer, and the weight percentage of the enteric layer is: 60-75% of the second film-forming material, 15-20% of the second plasticizer and 4-20% of the anti-adhesive agent.

[0035] Preferably, the first filler is one or more combinations of lactose, microcrystalline cellulose, mannitol, and sucrose, preferably a combination of microcrystalline cellulose and sucrose; the first sustained-release matrix material is one or more combinations of hydroxypropyl methylcellulose, polyethylene oxide, and polyacrylic acid resin, preferably hydroxypropyl methylcellulose; the first binder is one or more combinations of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone, preferably hydroxypropyl cellulose; the first lubricant is one or more combinations of magnesium stearate and sodium stearyl fumarate, preferably magnesium stearate; the first film-forming material is hydroxypropyl methylcellulose, polyethylene The first plasticizer is one or more combinations of polyethylene glycol, triethyl citrate, and polysorbate, preferably polyethylene glycol; the second film-forming material is one or more combinations of polyacrylic acid resin and hydroxypropyl methylcellulose phthalate, preferably polyacrylic acid resin; the second plasticizer is one or more combinations of polyethylene glycol, triethyl citrate, and polysorbate, preferably polyethylene glycol; the anti-adhesive agent is one or more combinations of talc, glyceryl monostearate, and glyceryl mono- and distearate, preferably glyceryl mono- and distearate.

[0036] Preferably, the weight percentage of each component of the drug-loaded pellets of the levodopa drug delivery system in the second pellet core is: 100% of the second pellet core and 6-10% of the first modified layer, wherein the weight percentage of the second pellet core is: 50-60% of the levodopa raw material, 5-24.5% of the second filler, 20-26% of the second sustained-release skeleton material, 5-8% of the second adhesive and 0.5-1.5% of the second lubricant, and the weight percentage of the first modified layer is: 75-85% of the third film-forming material and 15-25% of the third plasticizer.

[0037] Preferably, the second filler is one or more combinations of lactose, microcrystalline cellulose, mannitol, and sucrose, preferably microcrystalline cellulose; the second sustained-release matrix material is one or more combinations of hydroxypropyl methylcellulose, polyethylene oxide, and polyacrylic acid resin, preferably hydroxypropyl methylcellulose; the second binder is one or more combinations of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone, preferably polyvinyl pyrrolidone; the second lubricant is one or more combinations of magnesium stearate and sodium stearyl fumarate, preferably magnesium stearate; the third film-forming material is one or more combinations of hydroxypropyl methylcellulose, polyvinyl alcohol, and hydroxyethyl cellulose, preferably hydroxypropyl methylcellulose; the third plasticizer is one or more combinations of polyethylene glycol, triethyl citrate, and polysorbate, preferably polyethylene glycol.

[0038] Preferably, the weight percentage of each component of the drug-loaded pellets of the carbidopa drug delivery system to the third pellet core is: 100% of the third pellet core and 6-10% of the second modified layer, wherein the weight percentage of the third pellet core is: 60-70% of the carbidopa raw material, 5-14.5% of the third filler, 17-23% of the third sustained-release skeleton material, 3-6% of the third adhesive and 0.5-1.5% of the third lubricant, and the weight percentage of the second modified layer is: 75-85% of the fourth film-forming material and 15-25% of the fourth plasticizer.

[0039] Preferably, the third filler is one or more combinations of lactose, microcrystalline cellulose, mannitol, and sucrose, preferably a combination of lactose and microcrystalline cellulose; the third sustained-release matrix material is one or more combinations of hydroxypropyl methylcellulose, polyethylene oxide, and polyacrylic acid resin, preferably polyacrylic acid resin; the third adhesive is one or more combinations of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone, preferably hydroxypropyl methylcellulose; the third lubricant is one or more combinations of magnesium stearate and sodium stearyl fumarate, preferably magnesium stearate; the fourth film-forming material is one or more combinations of hydroxypropyl methylcellulose and polyvinyl alcohol, preferably polyvinyl alcohol; the fourth plasticizer is one or more combinations of polyethylene glycol, triethyl citrate, and polysorbate, preferably triethyl citrate.

[0040] The above-mentioned excipients are all commonly used types of oral solid preparations, with strong accessibility and stable performance.

[0041] Lactose is a commonly used filler for oral solid preparations, suitable for dry granulation and direct compression of powders. α-lactose monohydrate or anhydrous lactose is usually selected. It is white or off-white crystalline granules or powder with good stability and compressibility. The commonly used dosage range in different independent drug release systems of the present invention is 0-90%.

[0042] Microcrystalline cellulose is a commonly used filler for oral solid preparations. It has a variety of models and is suitable for different usage environments and processes, such as wet granulation, direct powder compression, dry granulation, etc. It is white or off-white crystalline particles or powder, has good stability, compressibility, and fluidity, and also has the function of a partial adhesive. The commonly used dosage range in different independent drug release systems of the present invention is 0-85%.

[0043] Mannitol is a commonly used filler for oral solid preparations. For wet granulation, the smaller particle size is usually selected, such as 25C, 50C, 120C, etc. It is white or off-white crystalline granules or powder, and has good stability and compressibility. The commonly used dosage range in different independent drug delivery systems of the present invention is 0-80%.

[0044] Sucrose is a commonly used filler for oral solid preparations. It is cheap and readily available, suitable for preparing pill cores, has good formability, and is a white or off-white crystalline powder. The commonly used amount in different independent drug release systems of the present invention ranges from 0 to 80%.

[0045] Hydroxypropyl cellulose is a commonly used binder and film-forming material for oral solid preparations. It is a white or off-white powder and is suitable for wet granulation and extrusion spheronization to prepare pellet cores. It has good adhesion and film-forming properties. It is divided into different types according to molecular weight and viscosity. The commonly used dosage range in different independent drug release systems in the present invention is 0-30%.

[0046] Hydroxypropyl methylcellulose is a commonly used excipient for oral solid preparations. It is a white or off-white powder and is classified into different types according to molecular weight and viscosity. It can be used for sustained-release skeleton materials, adhesives and film-forming materials. The commonly used dosage range in different independent drug release systems of the present invention is 0-50%.

[0047] Polyvinylpyrrolidone is a commonly used binder for oral solid preparations. It is an off-white powder and is suitable for wet granulation and extrusion spheronization to prepare pellet cores. It has good adhesion and is divided into different types according to molecular weight and viscosity. The common range is 0-30%.

[0048] Polyoxyethylene is a commonly used sustained-release skeleton material for oral solid preparations. It is an off-white powder and is divided into different types according to molecular weight and viscosity. Different types produce different blocking effects and are suitable for products with different release requirements. In the present invention, the commonly used dosage range in different independent drug release systems is 0-60%.

[0049] Polyacrylic acid resin is a polymer resin solid preparation auxiliary material, which is divided into different types according to molecular weight and structural formula. It is suitable for sustained-release skeleton materials, enteric materials, and sustained-release film-forming materials. The commonly used dosage range in different independent drug release systems of the present invention is 0-50%.

[0050] Magnesium stearate and sodium stearyl fumarate are commonly used lubricants to improve the fluidity and compressibility of materials and prevent sticking during tableting. The commonly used amount in different independent drug release systems of the present invention is in the range of 0.5-5%.

[0051] Polyvinyl alcohol is a commonly used film-forming material for oral solid preparations. It is a white or off-white powder with good film-forming properties. It is classified into different types according to molecular weight and viscosity. The commonly used dosage range in different independent drug release systems of the present invention is 0-30%.

[0052] Hydroxyethyl cellulose is a commonly used film-forming material for oral solid preparations. It is a white or off-white powder with good film-forming properties. It is classified into different types according to molecular weight and viscosity. The commonly used dosage range in different independent drug release systems of the present invention is 0-20%.

[0053] Hydroxypropyl methylcellulose phthalate is a commonly used enteric film-forming material for oral solid preparations. It is a white or off-white powder with good film-forming properties. It has a variety of different types and has the function of breaking the film under different pH conditions. Different types can be selected according to the needs of the preparation products. The commonly used dosage range in different independent drug release systems in the present invention is 0-35%.

[0054] Polyethylene glycol, triethyl citrate and polysorbate are commonly used plasticizers in coating processes to increase the plasticity and ductility of the coating layer.

[0055] Talc, glyceryl monostearate, and glyceryl mono- and distearate are commonly used anti-sticking agents in coating processes. They are used to reduce the viscosity of film-forming materials during the coating process, increase their ductility on the material surface, and make film formation more uniform.

[0056] A method for preparing the above-mentioned multi-system drug release system for treating Parkinson's disease comprises the following steps:

[0057] (1) Preparation of Entacapone Delivery System

[0058] The first pellet cores are granulated by an extrusion spheronization device, and the dried first pellet cores are transferred to a wurster coating device to coat the first pellet cores with an isolation layer, and then the isolation layer is coated with an enteric layer in the wurster coating device to obtain drug-loaded pellets of the entacapone drug delivery system;

[0059] (2) Preparation of Levodopa Drug Delivery System

[0060] Granulate the second pellet cores by using an extrusion spheronization device, transfer the dried second pellet cores to a wurster coating device, and coat the second pellet cores with a first modification layer to obtain drug-loaded pellets of a levodopa drug delivery system;

[0061] (3) Preparation of carbidopa delivery system

[0062] Granulate the third pellet cores by using an extrusion spheronization device, transfer the dried third pellet cores to a wurster coating device, and coat the third pellet cores with a second modification layer to obtain drug-loaded pellets of a carbidopa drug delivery system;

[0063] (4) Preparation of capsules

[0064] The entacapone drug delivery system loaded micropellets, the levodopa drug delivery system loaded micropellets, the carbidopa drug delivery system loaded micropellets and talcum powder are uniformly mixed in a weight percentage ratio of 58.0-64.1%, 28.5-31.5%, 7.6-8.4% and 0.5-1.5%, respectively, and then capsule filling is performed to prepare capsules.

[0065] Compared with the prior art, the present invention has the following advantages: the multi-system drug release system of the present invention includes three independent drug release systems, which can effectively improve the stability and bioavailability of entacapone in vivo, solve the problem that entacapone is unstable in gastric acid and cannot be released for a long time, and realize the independent release of three different active ingredients of entacapone, levodopa and carbidopa without interfering with each other, and also realize the purpose of long-term slow release of the three active ingredients, so as to better play the clinical therapeutic effect of Parkinson's disease and meet the release requirements for treatment and maximum cost-effectiveness. The preparation method of the multi-system drug release system of the present invention is a high-load preparation method, which uses extrusion spheronization and wurster coating technology to prepare a multi-system drug release system with stable performance and independent drug release system, which can effectively solve the problem of large doses of drugs, and the production process is mature and stable, with good feasibility, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 It is the dissolution curve diagram of Example 1 and Comparative Examples 1-3. DETAILED DESCRIPTION

[0067] The present invention will be further described below in conjunction with specific examples. It should be understood that the following examples are only for the purpose of illustrating the present invention and are not intended to limit the contents thereof.

[0068] Example 1: A multi-system drug delivery system for the treatment of Parkinson's disease, wherein the multi-system drug delivery system is a capsule prepared from the following drug delivery systems and excipients in the following weight percentage ratios: 61% of entacapone drug delivery system, 30% of levodopa drug delivery system, 8% of carbidopa drug delivery system and 1% of talc. The multi-system drug delivery system for the treatment of Parkinson's disease is prepared according to the composition shown in Table 1, comprising the following steps:

[0069] (1) Preparation of Entacapone Delivery System

[0070] The first binder hydroxypropyl cellulose is prepared into an aqueous binder solution for standby use;

[0071] Add the micronized entacapone API, the first filler microcrystalline cellulose and sucrose, the first sustained-release matrix material hypromellose, and the first lubricant magnesium stearate into a wet granulation device and mix them evenly;

[0072] A water-based adhesive solution is sprayed into the uniformly mixed material to prepare a soft material;

[0073] The soft material is transferred to an extrusion spheronization device, and the first pellet core is granulated by the extrusion spheronization device. The dried first pellet core is transferred to a wurster coating device, and the first pellet core is coated with an isolation layer. Then, the isolation layer is coated with an enteric layer in the wurster coating device to obtain drug-loaded micropellets of an entacapone drug delivery system, wherein the weight percentage of each component of the drug-loaded micropellets of the entacapone drug delivery system to the first pellet core is: 100% of the first pellet core, 6-10% of the isolation layer, and 10-23% of the enteric layer;

[0074] (2) Preparation of Levodopa Drug Delivery System

[0075] The second adhesive polyvinylpyrrolidone is prepared into an aqueous adhesive solution for standby use;

[0076] Add the micronized levodopa API, the second filler microcrystalline cellulose, the second sustained-release matrix material hypromellose, and the second lubricant magnesium stearate into the wet granulation equipment and mix them evenly;

[0077] A water-based adhesive solution is sprayed into the uniformly mixed material to prepare a soft material;

[0078] The soft material is transferred to an extrusion spheronization device, and the second pellet core is granulated by the extrusion spheronization device. The dried second pellet core is transferred to a wurster coating device, and the second pellet core is coated with a first modification layer to obtain drug-loaded micropellets of a levodopa drug delivery system, wherein the weight percentage of each component of the drug-loaded micropellets of the levodopa drug delivery system to the second pellet core is: 100% of the second pellet core and 6-10% of the first modification layer;

[0079] (3) Preparation of carbidopa delivery system

[0080] The third binder, hydroxypropyl methylcellulose, is prepared into an aqueous binder solution for later use;

[0081] Add the micronized carbidopa API, the third filler microcrystalline cellulose and sucrose, the third sustained-release matrix material polyacrylic acid resin, and the third lubricant magnesium stearate into a wet granulation device and mix them evenly;

[0082] A water-based adhesive solution is sprayed into the uniformly mixed material to prepare a soft material;

[0083] The soft material is transferred to an extrusion spheronization device, and the third pellet core is granulated by the extrusion spheronization device. The dried third pellet core is transferred to a wurster coating device, and the third pellet core is coated with a second modification layer to obtain drug-loaded micropellets of a carbidopa drug delivery system. The weight percentage of each component of the drug-loaded micropellets of the carbidopa drug delivery system to the third pellet core is: 100% of the third pellet core and 6-10% of the second modification layer;

[0084] (4) Preparation of capsules

[0085] The entacapone drug delivery system loaded micropellets, the levodopa drug delivery system loaded micropellets, the carbidopa drug delivery system loaded micropellets and talcum powder were mixed uniformly in a weight percentage ratio of 61%, 30%, 8% and 1%, respectively, and then filled into gelatin hollow capsules to prepare capsules.

[0086] Table 1: Composition of the multi-system drug delivery system of Example 1

[0087]

[0088] Comparative Example 1: The multi-system drug delivery system of Comparative Example 1 is different from Example 1 only in that the drug-loaded micropellets of the entacapone drug delivery system of Comparative Example 1 are not designed with an enteric layer.

[0089] Comparative Example 2: Micronized entacapone API, levodopa API, carbidopa API and other excipients were prepared into tablet cores and coated with conventional processes to prepare tablet drugs. The preparation process is: the components of the tablet core shown in Table 2 were prepared into soft materials by wet granulation process, and then the soft materials were transferred to a fluidized bed for drying and granulation, and then the dry granules were mixed, and then tableted, and then coated to increase the weight to 3%. The composition of the tablet drugs of Comparative Example 2 is shown in Table 2.

[0090] Table 2: Composition of the tablet drug of Comparative Example 2

[0091]

[0092] Comparative Example 3: The micronized entacapone API and other excipients are prepared into the entacapone part material by conventional process, and the micronized levodopa API, carbidopa API and other excipients are prepared into the levodopa / carbidopa part material by conventional process, and then the above two materials are double-layered to prepare double-layer tablets, and the double-layer tablets are film-coated to obtain double-layer tablet drugs. The preparation process is:

[0093] 1) Entacapone part: The micronized entacapone API shown in Table 3 and other excipients are prepared into a soft material by conventional wet granulation process, and then the soft material is transferred to a fluidized bed for drying and granulation, and then the dry granules are mixed to obtain the material of the entacapone part;

[0094] 2) Levodopa / carbidopa portion: The micronized levodopa API, carbidopa API and other excipients shown in Table 3 are prepared into a soft material by conventional wet granulation process, and then the soft material is transferred to a fluidized bed for drying and granulation, and then the dry granules are mixed to obtain the levodopa / carbidopa portion of the material;

[0095] 3) performing double-layer tableting of the entacapone part material and the levodopa / carbidopa part material to obtain a double-layer tablet;

[0096] 4) Film coating of the bilayer tablets.

[0097] Table 3: Composition of the bilayer tablet drug of Comparative Example 3

[0098]

[0099] Table 4: Design purpose and verification method of the embodiments and comparative examples

[0100]

[0101] The purpose and verification method of the above embodiments and comparative examples are shown in Table 4, wherein the verification method and results are as follows:

[0102] (1) Forced destruction experiment

[0103] The samples of the above examples and comparative examples were selected, and destroyed in 0.1N hydrochloric acid in a 60°C water bath for 1 hour, and then ultrasonicated or shaken to make the solution uniform, and then centrifuged to obtain the supernatant, and the impurities were detected using a high performance liquid chromatograph. The test results are shown in Table 5:

[0104] Table 5: Test results of forced destruction experiment

[0105] Impurities Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Maximum single impurity 0.08％ 2.12％ 3.43％ 3.04％ Total Miscellaneous 0.17％ 8.19％ 10.12％ 9.67％

[0106] The results showed that using an enteric layer to protect entacapone can effectively prevent the destruction of entacapone by acidic conditions.

[0107] (2) Dissolution test

[0108] The dissolution test method, conditions and detection method are shown in Table 6, the test results are shown in Table 7, and the dissolution curve is shown in Figure 1 .

[0109] Table 6: Dissolution test methods, conditions and detection methods

[0110]

[0111] Table 7: Dissolution test results

[0112]

[0113] The test results of the above forced destruction test and dissolution test show that:

[0114] 1. Products without enteric layer protection will cause different degrees of degradation of entacapone after being soaked in acidic solution, resulting in a low final dissolution amount of entacapone;

[0115] 2. The drug prepared by the independent drug release system of the present invention has a smoother release curve, stronger uniformity and smaller intra-batch difference; on the contrary, the product that integrates the main components such as entacapone, levodopa and carbidopa into one release system has a greater difference in release curve, a faster release rate, and no significant long-term sustained release effect, which will have an adverse effect on the release of the drug in the body and the improvement of bioavailability.

Claims

1. A multi-system drug delivery system for the treatment of Parkinson's disease, characterized in that: The multi-system drug release system is a capsule prepared from drug release systems and excipients in the following weight percentages: 58.0-64.1% of entacapone drug release system, 28.5-31.5% of levodopa drug release system, 7.6-8.4% of carbidopa drug release system and 0.5-1.5% of talcum powder, wherein the entacapone drug release system, the levodopa drug release system and the carbidopa drug release system are respectively composed of drug-loaded micropellets, the drug-loaded micropellets of the entacapone drug release system include a first core, an isolation layer and an enteric layer arranged in sequence from the inside to the outside, the first core contains entacapone raw material, the drug-loaded micropellets of the levodopa drug release system include a second core and a first modified layer arranged in sequence from the inside to the outside, the second core contains levodopa raw material, and the drug-loaded micropellets of the carbidopa drug release system include a third core and a second modified layer arranged in sequence from the inside to the outside, the third core contains carbidopa raw material.

2. The multi-system drug delivery system for treating Parkinson's disease according to claim 1, characterized in that: The weight percentage of each component of the drug-loaded micro-pellet of the entacapone drug delivery system is as follows: 100% of the first pill core, 6-10% of the isolation layer and 10-23% of the enteric layer, wherein the weight percentage of the first pill core is as follows: 40-60% of the entacapone raw material, 5-34.5% of the first filler, 20-26% of the first sustained-release skeleton material, 5-8% of the first adhesive and 0.5-1.5% of the first lubricant, the weight percentage of the isolation layer is as follows: 75-85% of the first film-forming material and 15-25% of the first plasticizer, and the weight percentage of the enteric layer is as follows: 60-75% of the second film-forming material, 15-20% of the second plasticizer and 4-20% of the anti-adhesive agent.

3. The multi-system drug delivery system for treating Parkinson's disease according to claim 2, characterized in that: The first filler is one or more combinations of lactose, microcrystalline cellulose, mannitol, and sucrose; the first sustained-release skeleton material is one or more combinations of hydroxypropyl methylcellulose, polyethylene oxide, and polyacrylic acid resin; the first adhesive is one or more combinations of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone; the first lubricant is one or more combinations of magnesium stearate and sodium stearyl fumarate; the first film-forming material is one or more combinations of hydroxypropyl methylcellulose, polyvinyl alcohol, and hydroxyethyl cellulose; the first plasticizer is one or more combinations of polyethylene glycol, triethyl citrate, and polysorbate; the second film-forming material is one or more combinations of polyacrylic acid resin and hydroxypropyl methylcellulose phthalate; the second plasticizer is one or more combinations of polyethylene glycol, triethyl citrate, and polysorbate; and the anti-adhesive is one or more combinations of talc, glyceryl monostearate, and glyceryl mono- and distearate.

4. The multi-system drug delivery system for treating Parkinson's disease according to claim 1, characterized in that: The weight percentage of each component of the drug-loaded pellets of the levodopa drug delivery system in the second pellet core is: 100% of the second pellet core and 6-10% of the first modified layer, wherein the weight percentage of the second pellet core is: 50-60% of the levodopa raw material, 5-24.5% of the second filler, 20-26% of the second sustained-release skeleton material, 5-8% of the second adhesive and 0.5-1.5% of the second lubricant, and the weight percentage of the first modified layer is: 75-85% of the third film-forming material and 15-25% of the third plasticizer.

5. The multi-system drug delivery system for treating Parkinson's disease according to claim 4, characterized in that: The second filler is one or more combinations of lactose, microcrystalline cellulose, mannitol, and sucrose; the second sustained-release matrix material is one or more combinations of hydroxypropyl methylcellulose, polyethylene oxide, and polyacrylic acid resin; the second adhesive is one or more combinations of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone; the second lubricant is one or more combinations of magnesium stearate and sodium stearyl fumarate; the third film-forming material is one or more combinations of hydroxypropyl methylcellulose, polyvinyl alcohol, and hydroxyethyl cellulose; and the third plasticizer is one or more combinations of polyethylene glycol, triethyl citrate, and polysorbate.

6. The multi-system drug delivery system for treating Parkinson's disease according to claim 1, characterized in that: The weight percentage of each component of the drug-loaded pellets of the carbidopa drug delivery system to the third pellet core is: 100% of the third pellet core and 6-10% of the second modified layer, wherein the weight percentage of the third pellet core is: 60-70% of the carbidopa raw material, 5-14.5% of the third filler, 17-23% of the third sustained-release skeleton material, 3-6% of the third adhesive and 0.5-1.5% of the third lubricant, and the weight percentage of the second modified layer is: 75-85% of the fourth film-forming material and 15-25% of the fourth plasticizer.

7. The multi-system drug delivery system for treating Parkinson's disease according to claim 6, characterized in that: The third filler is one or more combinations of lactose, microcrystalline cellulose, mannitol, and sucrose; the third sustained-release skeleton material is one or more combinations of hydroxypropyl methylcellulose, polyethylene oxide, and polyacrylic acid resin; the third adhesive is one or more combinations of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and polyvinyl pyrrolidone; the third lubricant is one or more combinations of magnesium stearate and sodium stearyl fumarate; the fourth film-forming material is one or more combinations of hydroxypropyl methylcellulose and polyvinyl alcohol; and the fourth plasticizer is one or more combinations of polyethylene glycol, triethyl citrate, and polysorbate.

8. A method for preparing a multi-system drug delivery system for treating Parkinson's disease according to any one of claims 1 to 7, characterized in that: The following steps are involved: (1) Preparation of Entacapone Delivery System The first pellet cores are granulated by an extrusion spheronization device, and the dried first pellet cores are transferred to a wurster coating device to coat the first pellet cores with an isolation layer, and then the isolation layer is coated with an enteric layer in the wurster coating device to obtain drug-loaded pellets of the entacapone drug delivery system; (2) Preparation of Levodopa Drug Delivery System Granulate the second pellet cores by using an extrusion spheronization device, transfer the dried second pellet cores to a wurster coating device, and coat the second pellet cores with a first modification layer to obtain drug-loaded pellets of a levodopa drug delivery system; (3) Preparation of carbidopa delivery system Granulate the third pellet cores by using an extrusion spheronization device, transfer the dried third pellet cores to a wurster coating device, and coat the third pellet cores with a second modification layer to obtain drug-loaded pellets of a carbidopa drug delivery system; (4) Preparation of capsules The entacapone drug delivery system loaded micropellets, the levodopa drug delivery system loaded micropellets, the carbidopa drug delivery system loaded micropellets and talcum powder are uniformly mixed in a weight percentage ratio of 58.0-64.1%, 28.5-31.5%, 7.6-8.4% and 0.5-1.5%, respectively, and then capsule filling is performed to prepare capsules.

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