A double gel medicine for treating Parkinson's disease and its preparation method and application

Abstract

The application discloses a double gel for treating Parkinson's disease and a preparation method and application thereof. The double gel comprises a hydrogel phase and an oil gel phase; the hydrogel phase comprises Fructus Physalis seed gum, xanthan gum, levodopa and carbidopa; the oil gel phase comprises camellia oil, white beeswax and entacapone; the levodopa and the carbidopa are loaded in the hydrogel phase, the entacapone is dispersed in the oil gel phase, and the hydrogel phase and the oil gel phase are compounded in a volume ratio of 1:1. The double gel is prepared by two phases, compounded by high-speed shearing and solidified at low temperature, can form a stable double gel structure, and can control the release of levodopa under in-vitro simulated gastrointestinal digestion conditions. The application is suitable for preparing a therapeutic drug for oral administration of Parkinson's disease patients with dysphagia.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation and drug delivery technology, specifically relating to a dual gel for the treatment of Parkinson's disease, its preparation method, and its application. Background Technology

[0002] Parkinson's disease is a common neurodegenerative disease whose development is mainly related to the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and a decrease in striatal dopamine levels. Patients mainly present with motor symptoms such as bradykinesia, rigidity, and resting tremor, and may also experience non-motor symptoms such as decreased sense of smell, sleep disturbances, and mood disorders.

[0003] Levodopa is an important drug in the current treatment of Parkinson's disease. After entering the central nervous system, levodopa is converted into dopamine, thereby replenishing dopamine levels in the brain. To reduce the metabolism of levodopa in peripheral tissues, it is often used clinically in combination with the dopa decarboxylase inhibitor carbidopa. Entacapone, a catechol-O-methyltransferase inhibitor, can further improve the utilization of levodopa by inhibiting its peripheral metabolism. Therefore, combination drugs consisting of levodopa, carbidopa, and entacapone are used in the treatment of Parkinson's disease.

[0004] Currently, levodopa combination drugs are mainly administered in oral solid dosage forms such as tablets and capsules. However, as Parkinson's disease progresses, some patients experience varying degrees of swallowing dysfunction. For patients with swallowing difficulties, traditional tablets or capsules may pose risks such as difficulty swallowing, drug retention, choking, or even aspiration. Patients crushing tablets or altering the original dosage form before taking the medication may also affect the drug release characteristics of the original formulation.

[0005] On the other hand, levodopa is eliminated from the body relatively quickly, and the release of the drug is relatively concentrated after administration of conventional oral formulations. As the disease progresses, the patient's tolerance range for changes in drug concentration may gradually decrease. Therefore, appropriate regulation of the release process of levodopa-like drugs is of practical significance.

[0006] Currently, there are several drug delivery protocols for Parkinson's disease, including enteric gel continuous infusion and subcutaneous continuous infusion. Enteric gel typically requires percutaneous endoscopic gastrostomy and continuous drug delivery into the small intestine via a catheter, while subcutaneous continuous infusion requires specific injection and infusion devices. While these methods achieve relatively continuous drug delivery, they suffer from drawbacks such as complex procedures, high invasiveness, or the need for specialized infusion equipment.

[0007] A bigel is a composite gel system consisting of a hydrogel phase and an olegel phase. Hydrogels typically form a three-dimensional network of hydrophilic polymers and can be used to load water-soluble or hydrophilic active substances; olegels, on the other hand, use an oil-phase gelling agent to form a semi-solid network of liquid oil, suitable for loading hydrophobic active substances. By combining hydrogels and olegels, active ingredients with different physicochemical properties can be simultaneously loaded into the same system.

[0008] However, different hydrogel materials, oil phase materials, oleoglycans, and the ratio of the two phases all significantly affect the gelation state, mechanical properties, adhesion, cohesion, rheological properties, oil droplet distribution, and swallowing characteristics of the bigel. For compound drugs containing levodopa, carbidopa, and entacapone, levodopa and carbidopa have strong hydrophilicity, while entacapone has poor water solubility. Therefore, how to select suitable hydrogel and oleoglycan systems, and load the three drugs into different gel phases according to their respective physicochemical properties, while ensuring the stability of the bigel structure and obtaining texture and rheological properties suitable for swallowing, still requires targeted formulation screening and system design.

[0009] Therefore, it is necessary to provide a dual gel suitable for levodopa, carbidopa and entacapone combination drugs, so that drugs with different physicochemical properties can be loaded into the hydrogel phase and oleogel phase respectively, and obtain better structural stability, swallowability and in vitro drug release regulation performance. Summary of the Invention

[0010] The purpose of this invention is to address the shortcomings of existing oral solid dosage forms for Parkinson's disease in terms of applicability to patients with dysphagia, as well as the differences in the physicochemical properties of levodopa, carbidopa, and entacapone, by providing a dual gel for the treatment of Parkinson's disease, its preparation method, and its application.

[0011] To achieve the above objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides a dual gel for the treatment of Parkinson's disease, the dual gel comprising a hydrogel phase and an oleogel phase; The oleogel phase includes camellia oil, white beeswax and entacapone, wherein, based on the oleogel phase, the mass fraction of white beeswax is 4% to 6%, and the entacapone is dispersed in the oleogel phase; The hydrogel phase includes pseudophyte seed gum, xanthan gum, levodopa and carbidopa, wherein, based on the hydrogel phase, the mass fraction of pseudophyte seed gum is 0.4%, the mass fraction of xanthan gum is 1.0% to 1.5%, and the levodopa and carbidopa are loaded in the hydrogel phase; The oleogel phase is dispersed in the hydrogel phase to form an oil-in-water bigel.

[0012] Furthermore, the volume ratio of the hydrogel phase to the olegel phase is 1:1.

[0013] Furthermore, the xanthan gum has a mass fraction of 1.5%, and the white beeswax has a mass fraction of 6%.

[0014] Furthermore, the mass ratio of the levodopa, carbidopa, and entacapone is 4:1:8.

[0015] Furthermore, the olegel phase is dispersed in the hydrogel phase in the form of oil droplets to form an oil-in-water bigel; the oil droplets include oil droplets with a particle size of 2 to 5 μm and oil droplets with a particle size greater than 100 μm.

[0016] Furthermore, under the conditions of 25°C, 1.0% fixed strain, and a frequency scanning of 0.1–10 Hz, the storage modulus G' of the dual gel is greater than the loss modulus G'', and the loss factor tanδ is 0.1–1.

[0017] Secondly, the present invention provides a method for preparing the above-mentioned dual-gel for treating Parkinson's disease, comprising the following steps: S1. Add levodopa and carbidopa to the crude extract of pseudophys seed gum, mix, add xanthan gum, and heat and stir to obtain a hydrogel phase loaded with levodopa and carbidopa. S2. Entacapone is dispersed in camellia oil, then white beeswax is added and heated to melt the white beeswax, to obtain an oleogel phase loaded with entacapone. S3. The hydrogel phase and olegel phase are mixed under heat preservation and subjected to high-speed shearing, followed by cooling and solidification to obtain the Parkinson's disease treatment drug dual gel.

[0018] Furthermore, the preparation method of the crude extract of Physalis alkekengi seed gum includes: mixing Physalis alkekengi seeds with deionized water at a mass-volume ratio of 1:10, extracting in a water bath at 80°C, filtering to remove the Physalis alkekengi seeds, and obtaining the crude extract of Physalis alkekengi seed gum.

[0019] Further, in step S1, levodopa and carbidopa are added to the crude extract of pseudophyte seed gum at 60°C; in step S2, entacapone is added to camellia oil at 60°C for dispersion, and white beeswax is added and heated to melt the white beeswax.

[0020] Furthermore, in step S3, intermittent shearing is performed at a rotation speed of 10,000 r / min, with a 20-second pause after every 1 minute of shearing, for a total shearing time of 5 minutes; after shearing, the material is allowed to stand and cure at 4°C for 24 hours.

[0021] Thirdly, the present invention provides the use of the dual gel described in the first aspect in the preparation of a medicament for treating Parkinson's disease.

[0022] Compared with the prior art, the present invention has at least the following beneficial effects: (1) In this invention, levodopa and carbidopa are loaded in the hydrogel phase of pseudoalgae seed gum-xanthan gum, and entacapone is loaded in the hydrogel phase of camellia oil-white beeswax oil, thus realizing phase-separated loading of hydrophilic drugs and hydrophobic drugs in the same dual gel system.

[0023] (2) The dual gel system of the present invention can form a stable semi-solid structure with good cohesion, viscoelasticity and swallowability, and is suitable as an oral drug carrier for Parkinson's disease patients with dysphagia.

[0024] (3) The dual gel of the present invention can change the concentration-time change characteristics of levodopa in the simulated gastric juice and simulated intestinal juice digestion stages, especially reducing the rapid release of levodopa in the early stage of simulated gastric juice digestion, and delaying the time of its highest detection concentration in the simulated gastric juice stage to about 120 min.

[0025] (4) The dual gel of the present invention can also change the release behavior of carbidopa and entacapone in the simulated gastric juice and simulated intestinal juice digestion stages, thereby achieving synergistic release regulation of the three drugs, levodopa, carbidopa and entacapone, under simulated gastrointestinal digestion conditions in vitro. Attached Figure Description

[0026] Figure 1 The figures show the drug concentration-time curves of the dual-gel group of the present invention and the commercially available entacapone and double dopamine tablets II group during the simulated gastric digestion stage. In the figures, A is the concentration-time curve of levodopa, B is the concentration-time curve of carbidopa, and C is the concentration-time curve of entacapone.

[0027] Figure 2 The figures show the drug concentration-time curves of the dual-gel group of the present invention and the commercially available entacapone and double dopamine tablets II group during the simulated intestinal digestion stage. In the figures, A is the concentration-time curve of levodopa, B is the concentration-time curve of carbidopa, and C is the concentration-time curve of entacapone. Detailed Implementation

[0028] The following examples are provided to further illustrate the present invention, but should not be construed as limiting the scope of protection of the present invention. Unless otherwise stated, the raw materials and reagents used in the examples of the present invention can be obtained through conventional commercial means, and the experimental methods used are conventional methods in the art unless otherwise specified.

[0029] For ease of description, in the following examples, false groundcherry seed gum is abbreviated as NPGP, carrageenan as CG, gelatin as GEL, xanthan gum as XG, gellan gum as GG, agar as AG, gum arabic as GA, citrus pectin as CP, and sodium alginate as SA; avocado oil as AO, olive oil as OO, walnut oil as WO, camellia oil as CO, and flaxseed oil as FO; glyceryl monostearate as GMS, white beeswax as WB, and ethyl cellulose as EC.

[0030] Example 1 Screening of hydrogel materials 1.1 Preparation of crude extract of Physalis alkekengi seed gum Deionized water was added at a mass-to-volume ratio of 1:10 to the seeds of Physalis alkekengi, and extraction was carried out in a water bath at 80°C.

[0031] After extraction, the NPGP crude extract was obtained by filtration through a 100-mesh gauze bag to remove false physalis seeds and other insoluble substances, and the filtrate was collected.

[0032] The measured concentration of NPGP in the crude NPGP extract was 0.412%, which will be used as 0.4% in the subsequent formulation description.

[0033] The obtained crude NPGP extract was used for subsequent screening and preparation of composite hydrogel systems.

[0034] 1.2 Preparation of candidate aqueous colloids and composite hydrogels Eight food-grade colloids, namely CG, GEL, XG, GG, AG, GA, CP, and SA, were selected as candidate aqueous phase colloids.

[0035] The candidate colloids were compounded with NPGP crude extract. The corresponding candidate colloids were added to the NPGP crude extract and magnetically stirred in an 80°C water bath to fully dissolve or uniformly disperse the candidate colloids. Then, the mixture was cooled at 4°C for 12 h to form a gel.

[0036] To evaluate the gelling ability of each candidate colloid, a concentration gradient of 0.10% to 4.00% was set for a single colloid; and a concentration gradient of 0.05% to 5.00% was set for the composite system formed by the candidate colloid and NPGP.

[0037] 1.3 Evaluation Methods for Aqueous Gels (1) Determination of critical gelling concentration The critical gelation concentration of each single colloid and composite colloid system was determined using the 45° glass bottle tilting method, with three replicates for each group.

[0038] (2) Texture property testing Texture properties were tested using a texture analyzer in TPA mode.

[0039] The TMS-Pro texture analyzer was used for testing. A 50 N force sensor was used, along with a general-purpose cylindrical probe with a diameter of 30 mm, a probe rise height of 10 mm, a sample deformation of 50%, a detection speed of 60 mm / min, a trigger force of 0.1 N, and two test cycles.

[0040] (3) Rheological property testing The tests were conducted using an MCR302 rotational rheometer.

[0041] A 50 mm aluminum parallel plate was used with a gap of 1000 μm. The test temperature was 25℃, the strain was 1.0%, and the frequency scanning range was 0.1~10 Hz.

[0042] Record the energy storage modulus G', loss modulus G'', and loss factor tanδ.

[0043] 1.4 Screening Results of Aqueous Colloids (1) GA Within the tested concentration range, GA mainly exhibited a thickening effect and failed to form a stable gel, therefore it is not suitable as a hydrogel phase material for the dual-gel system of this invention.

[0044] (2) CP and SA Both CP and SA require Ca 2+ It participates in cross-linking to form a gel, and the resulting gel is a thermally irreversible gel.

[0045] Since the subsequent preparation of the dual gel requires compounding and homogenization at higher temperatures, using thermally irreversible gels is not conducive to the preparation of the dual gels. Therefore, the CP-NPGP system and the SA-NPGP system were excluded.

[0046] (3) CG-NPGP composite hydrogel The critical gelling concentration of the CG-NPGP composite system is 0.05%, which is relatively low.

[0047] However, as the CG concentration increases, the resulting gel hardness increases significantly, while its cohesiveness decreases, making it more prone to breakage under external force. For individuals with swallowing disorders, the formation of small particles from gel breakage may increase the risk of bolus disintegration during swallowing. Therefore, the CG-NPGP system is not the preferred hydrogel system.

[0048] (4) GEL-NPGP composite hydrogel The critical gelling concentration of the GEL-NPGP composite system is 4%.

[0049] The gel formed by this system has relatively high hardness, adhesiveness, and chewability. The overall texture of the gel is relatively hard and has high adhesion, which is not conducive to swallowing by people with swallowing disorders. Therefore, it is not a preferred hydrogel system.

[0050] (5) GG-NPGP composite hydrogel The critical gelling concentration of the GG-NPGP composite system is approximately 0.1%.

[0051] This system has strong elasticity and a low loss factor tanδ, exhibiting obvious elastic gel characteristics. The gel is generally hard and has relatively insufficient deformation ability during oral cavity and swallowing. Therefore, it is not a preferred hydrogel system.

[0052] (6) AG-NPGP composite hydrogel The critical gelling concentration of the AG-NPGP composite system is approximately 0.4%.

[0053] The gel network formed by this system is relatively loose and lacks elasticity, making it difficult to form a continuous food mass with good integrity. Therefore, it is not a preferred hydrogel system.

[0054] (7) XG-NPGP composite hydrogel The XG-NPGP composite system can form a self-supporting gel at a xanthan gum concentration of 0.75%.

[0055] Texture testing showed that the XG-NPGP composite hydrogel had low hardness, with a hardness of approximately 0.195 N at higher concentrations. The overall texture of the gel was soft and had low chewiness.

[0056] Rheological performance test results show that the loss factor tanδ of the XG-NPGP composite hydrogel is stably in the range of 0.1 to 1, exhibiting a weak gel state with elasticity as the main characteristic and a certain degree of viscosity.

[0057] This system can maintain a certain integrity of the food bolus during swallowing and can also deform appropriately when subjected to external force, which is conducive to the transport of the food bolus in the oral cavity and pharynx.

[0058] Based on a comprehensive consideration of critical gelation concentration, textural properties, and rheological properties, XG-NPGP composite hydrogel was determined as the preferred hydrogel phase of the dual-gel system of this invention.

[0059] Example 2 Screening of oil-phase gel materials 2.1 Screening of vegetable oils AO, OO, WO, CO and FO were selected as candidate oil phase materials.

[0060] An electronic nose was used to evaluate the volatile odor characteristics of different vegetable oils, and HPLC was used to determine the solubility of entacapone in different vegetable oils.

[0061] 2.2 Evaluation results of different vegetable oils FO has a high volatile response value and a noticeable oxidative odor, which is not suitable as a dual-gel matrix for drugs that need to be taken orally directly, so it was excluded.

[0062] OO and WO have higher responses to aromatic and sulfur volatile compounds, and their overall odor composition is more complex, so they were not chosen as preferred oil phases.

[0063] AO has a mild odor, and the solubility of entacapone in AO is 0.013383 mg / mL.

[0064] CO has a relatively neutral odor and good oxidative stability. The solubility of entacapone in CO is 0.014525 mg / mL, which is higher than its solubility in AO.

[0065] Based on the combined characteristics of vegetable oil odor, oxidative stability, and oil phase compatibility of entacapone, CO was determined as the oil phase matrix of the oleogel phase of this invention.

[0066] 2.3 Screening of oleogels Using CO as the oil phase, GMS, WB, and EC were selected as candidate oleogels.

[0067] The corresponding oleogel is added to CO, and the oleogel is fully melted or dispersed under heating conditions, and then cooled and molded at 4°C.

[0068] The apparent morphology, oil separation, and oil retention properties of different olegels were observed, and the critical gelation concentration was determined.

[0069] 2.4 Screening Results of Olegels (1) EC The critical gelling concentration of EC is about 8%, and the temperature required for its phase transition or processing is relatively high, exceeding 130°C; at the same time, the resulting oleogel has poor oil retention capacity and obvious oil separation can be observed, so it is not a preferred oleogel agent of the present invention.

[0070] (2) GMS GMS can induce CO to form oleogels with a critical gelling concentration of less than 5%. However, the resulting oleogels have weaker oil-holding capacity than the WB system and have a certain fatty odor, so they are not preferred as oleogel agents.

[0071] (3) WB During the WB pre-screening process, initial mass fractions of 1%, 2%, and 3% were set. The results showed that the CO-WB system could not form a stable oleogel that met the requirements for subsequent preparation of composite bigels at these concentrations. Further increasing the WB mass fraction enhanced the gel-forming ability of the system. Specifically, an oleogel could be formed at 4°C with a WB mass fraction of 4%, and at room temperature with a WB mass fraction of 6%.

[0072] WB can form a relatively uniform and stable oleogel system with CO, with good oil retention capacity and almost no obvious oil separation on a macroscopic scale. In addition, WB itself has a weak odor.

[0073] The oleogel formed by WB can maintain a stable gel state at lower temperatures and soften to a certain extent when it approaches body temperature, which is beneficial for subsequent drug release.

[0074] Based on the above pre-screening results, in the subsequent screening of composite dual-gel systems, WB mass fractions of 4% and 6% were selected as two representative low and high concentration groups to evaluate the effects of WB content on the apparent state, textural properties, rheological properties and swallowability of the dual gels.

[0075] Considering the gelling properties, oil holding capacity, odor, and processing performance, WB was selected as the oleogeling agent, and the CO-WB system was selected as the preferred oleogel phase in this invention.

[0076] Example 3 Screening of composite dual-gel systems 3.1 Dual-gel formulation setup Based on the screening results of Examples 1 and 2, and combined with the gelation and textural properties of different composite hydrogel systems, three composite hydrogel systems, namely CG-NPGP, GEL-NPGP and XG-NPGP, were selected to be composited with the CO-WB oleogel system respectively.

[0077] Set the following concentration gradient.

[0078] (1) Concentration gradient of hydrogel phase In the CG-NPGP system, the CG mass fractions were 0.075%, 0.100%, and 0.125%, respectively.

[0079] In the GEL-NPGP system, the GEL mass fractions are 4%, 5%, and 6%, respectively.

[0080] In the XG-NPGP system, the XG mass fractions are 1.0%, 1.25%, and 1.5%, respectively.

[0081] In each group, the crude NPGP extract was used as the fixation matrix.

[0082] (2) Concentration gradient of oleogel phase In CO-WB oleogels, the mass fractions of WB were set to 4% and 6%, respectively.

[0083] Therefore, this embodiment sets up a total of 18 dual-gel combinations, consisting of 3 hydrogel systems × 3 hydrogel concentrations × 2 WB concentrations.

[0084] The volume ratio of hydrogel phase to olegel phase in each group was 1:1.

[0085] 3.2 Preparation of bigels The corresponding composite hydrogels and CO-WB oleogels were prepared respectively.

[0086] The composite hydrogel was magnetically stirred in an 80°C water bath to ensure that the hydrogel components were fully dissolved or uniformly dispersed, and then kept warm for later use.

[0087] CO-WB oleogel was prepared in an 80°C water bath to fully melt WB in CO, resulting in a uniform oleogel preparative solution, which was then kept warm for later use.

[0088] The hydrogel phase and olegel phase were mixed at a volume ratio of 1:1 under heat preservation conditions, and intermittent shearing was performed using a high-speed homogenizer at 10,000 r / min.

[0089] The specific cutting method is as follows: cut for 1 minute, pause for 20 seconds, and then continue cutting, with a total cutting time of 5 minutes.

[0090] After shearing, the resulting sample was transferred to a 4°C environment and allowed to stand for 24 hours to cure, resulting in a double gel sample.

[0091] Preliminary experimental observations show that the ratio of the hydrogel phase to the oleogel phase affects the apparent state and textural characteristics of the dual gels. When the proportion of the hydrogel phase increases, the textural characteristics of the resulting system are closer to those of a hydrogel, and when the proportion of the oleogel phase increases, the textural characteristics of the resulting system are closer to those of an oleogel. Considering the dual gel forming state, structural stability, and swallowability, this embodiment uses a 1:1 volume ratio of hydrogel phase to oleogel phase for composite formation.

[0092] Preliminary experimental observations also showed that increasing the homogenization rotation speed is beneficial for enhancing the mixing uniformity of the hydrogel and olegel phases and affects the dispersion state of the olegel phase in the hydrogel phase. In this embodiment, intermittent shearing at 10000 r / min was used to obtain a more uniform bigel system.

[0093] 3.3 Two-Gel Evaluation Method (1) Observation of appearance and morphology Observe whether the obtained double gel sample is uniform and whether there is obvious oil separation, phase separation, cracking or fragmentation.

[0094] (2) TPA full texture test The TMS-Pro texture analyzer was used for testing, and the method of use was the same as in Example 1.3. The test indicators included breaking force, adhesion, elasticity, cohesion, chewiness and adhesiveness.

[0095] (3) Rheological property testing The tests were conducted using an MCR302 rotational rheometer. The test method is the same as in Example 1.3.

[0096] (4) Cryo-scanning electron microscopy observation The microstructure of the dual gel was observed using cryo-scanning electron microscopy (Cryo-SEM).

[0097] The samples were rapidly frozen with liquid nitrogen, followed by low-temperature fracture and sublimation to observe the aqueous network structure and oil droplet distribution in the sample cross-section.

[0098] (5) IDDSI spoon tilt test The swallowing fit of the obtained dual gels was evaluated using the spoon tilting method recommended by the International Dietary Standardization Initiative for Dysphagia (IDDSI).

[0099] Use a standard spoon to scoop up the sample, hold the spoon horizontally and slowly tilt it to almost vertical, observe whether the sample can maintain its overall shape and slide off the spoon, and at the same time observe the residue on the spoon surface and whether the sample is broken.

[0100] 3.4 Evaluation results of appearance and morphology (1) CG-NPGP-CO-WB system When the WB mass fraction was 4%, the low and medium concentration groups with CG mass fractions of 0.075% and 0.100% showed obvious phase separation and oil phase floating phenomenon.

[0101] When the CG mass fraction is increased to 0.125%, a relatively uniform semi-solid system can be formed.

[0102] When the WB mass fraction is increased to 6%, the phase separation is reduced. When the CG mass fraction is above 0.100%, a relatively uniform semi-solid system can be formed, but there is still a certain degree of oil separation in the low CG concentration group.

[0103] (2) GEL-NPGP-CO-WB system All concentrations of the GEL-NPGP-CO-WB system can form gels, but the overall texture is hard and brittle, and it is easy to break under external force.

[0104] Meanwhile, the system has poor thixotropic recovery after shearing, making it difficult to reform continuous and complete gel masses.

[0105] (3) XG-NPGP-CO-WB system Under the conditions of XG mass fractions of 1.0%, 1.25%, and 1.5% and WB mass fractions of 4% and 6%, the XG-NPGP-CO-WB system can form a relatively uniform semi-solid bigel.

[0106] No obvious macroscopic phase separation or oil precipitation was observed in the obtained sample. It had strong overall plasticity and a viscous, smooth texture.

[0107] 3.5 Evaluation Results of Texture Properties The TPA test results show that the WB concentration has a significant impact on the texture of the bigel.

[0108] Under the condition of 6% WB mass fraction, the overall breaking force, adhesion, cohesion, chewing properties and adhesiveness of the bigel are higher than those of the corresponding system with 4% WB mass fraction.

[0109] Among them, the XG-NPGP-CO-WB bigel with an XG mass fraction of 1.5% and a WB mass fraction of 6% exhibits high cohesiveness, indicating that the system can maintain a continuous bolus structure well under swallowing-related external forces and is not prone to disintegration or breakage.

[0110] Based on all textural parameters, the textural properties of this group of dual gels are within a range suitable for swallowing.

[0111] 3.6 Microstructure Evaluation Results Cryo-SEM observations showed that the bigels formed by different hydrogel systems had different microstructures.

[0112] The hydrogel network of the CG-NPGP-CO-WB bigel exhibits a distinct honeycomb-like, highly oriented ordered structure. This oriented structure is somewhat brittle and is prone to breakage along the orientation direction when subjected to external force.

[0113] The aqueous network of the XG-NPGP-CO-WB bigel exhibits an irregular interlaced structure.

[0114] Especially under the conditions of XG mass fraction of 1.5% and WB mass fraction of 6%, the oleogel phase is dispersed in the form of oil droplets in the continuous aqueous phase network. The oil droplets exhibit a distinct dual-state particle size distribution, including a large number of small oil droplets with a particle size of about 2 to 5 μm and some large oil droplets with a particle size greater than 100 μm.

[0115] Among them, a large number of tiny oil droplets are beneficial to enhancing the aqueous network structure, while some larger oil droplets can provide a certain lubrication effect, so that the resulting double gel can simultaneously take into account both the integrity of the aggregate and lubricity.

[0116] 3.7 Rheological performance evaluation results Rheological property test results show that in the preferred bigel system with XG mass fraction of 1.5% and WB mass fraction of 6%, the storage modulus G' is always greater than the loss modulus G'' within the tested frequency range.

[0117] The loss factor tanδ of this system is approximately 0.3 and remains stable in the range of 0.1 to 1.

[0118] G' being greater than G'' indicates that the obtained double gel has obvious elastic gel properties and can maintain a certain overall structure when subjected to external force; tanδ being in the range of 0.1 to 1 indicates that the system has both a certain viscosity and deformation capacity, which is beneficial for the gel to undergo appropriate deformation and be transported to the pharynx during swallowing.

[0119] 3.8 Results of the IDDSI spoon tilt test In the CG-NPGP-CO-WB system with a WB mass fraction of 4%, obvious stratification was observed in the low and medium CG concentration groups, and the samples could not slide off completely, leaving a lot of residue on the surface of the spoon; swallowability was only improved at higher CG concentrations combined with 6% WB.

[0120] The GEL-NPGP-CO-WB system is prone to breakage when the spoon is tilted, and the sample forms multiple small gel blocks that fall off separately, instead of forming a complete and continuous clump.

[0121] The XG-NPGP-CO-WB system can maintain its overall shape and slide completely off the spoon when it is tilted. Among them, the XG-NPGP-CO-WB dual gel with an XG mass fraction of 1.5% and a WB mass fraction of 6% leaves only a very small amount of residue on the spoon surface after it slides completely off, showing good swallowing adaptability.

[0122] 3.9 Determination of the optimal bigel formulation Based on the apparent morphology, textural properties, rheological properties, microstructure, and IDDSI spoon tilting test results of the dual gels, the XG-NPGP-CO-WB system was determined as the preferred dual gel system of this invention.

[0123] The preferred formulation is as follows: the mass fraction of NPGP in the hydrogel phase is 0.4%, and the mass fraction of XG is 1.5%; the oleogel phase uses CO as the oil phase matrix and the mass fraction of WB is 6%; the volume ratio of the hydrogel phase to the oleogel phase is 1:1.

[0124] The preferred preparation conditions are as follows: the hydrogel phase and the olegel phase are mixed under heat preservation conditions and composited by intermittent shearing at 10000 r / min for a total shearing time of 5 min; after shearing, the mixture is allowed to stand and cure at 4℃ for 24 h.

[0125] Example 4: Preparation of Drug Formulation and Drug Double Gel 4.1 Drug Prescription The XG-NPGP-CO-WB dual gel obtained in Example 3 was used as a carrier for levodopa, carbidopa, and entacapone.

[0126] Among them, levodopa and carbidopa were added to the hydrogel phase, and entacapone was added to the oleogel phase.

[0127] In this embodiment, based on the final preparation of 10 mL of drug double gel, the dosage of levodopa, carbidopa and entacapone were 100 mg, 25 mg and 200 mg, respectively, corresponding to final concentrations of 10 mg / mL, 2.5 mg / mL and 20 mg / mL.

[0128] The drug prescriptions and addition conditions are shown in Table 1.

[0129] Table 1 Drug prescription and addition conditions

[0130] The feed ratio of L-DOPA, Carbidopa, and Entacapone is 4:1:8.

[0131] 4.2 Preparation of hydrogel phases containing levodopa and carbidopa Take the crude NPGP extract and add 100 mg of levodopa and 25 mg of carbidopa at 60°C. Stir the mixture to fully dissolve and / or uniformly disperse the levodopa and carbidopa in the crude NPGP extract.

[0132] XG was then added to bring the mass fraction of XG in the hydrogel phase to 1.5%.

[0133] Continue stirring to fully dissolve XG and form a homogeneous composite hydrogel system with NPGP, thus obtaining an XG-NPGP hydrogel phase loaded with levodopa and carbidopa.

[0134] 4.3 Preparation of entacapone oleogel phase Take CO, add 200 mg of entacapone at 60°C, and stir continuously in a water bath to ensure that the entacapone is evenly dispersed in the CO.

[0135] Subsequently, WB was added to achieve a WB mass fraction of 6% in the oleogel phase. The WB was then heated to fully melt and uniformly disperse in CO, resulting in a CO-WB oleogel phase loaded with entacarbon.

[0136] 4.4 Compounding and Shaping of Drug Digels The XG-NPGP hydrogel phase loaded with levodopa and carbidopa and the CO-WB oleogel phase loaded with entacapone were mixed at a volume ratio of 1:1.

[0137] Under heat preservation conditions, intermittent shearing was performed using a high-speed homogenizer at a speed of 10,000 r / min.

[0138] The specific cutting method is as follows: after cutting continuously for 1 minute, pause for 20 seconds, and then repeat the above process. The total cutting time is 5 minutes.

[0139] After shearing, the resulting homogeneous system was transferred to 4°C and allowed to stand for 24 hours to cure, resulting in a double gel of Parkinson's disease treatment drugs loaded with levodopa, carbidopa, and entacapone.

[0140] Example 5: Evaluation of the in vitro simulated gastrointestinal digestion and drug release performance of the drug dual gel. 5.1 Experimental Samples and Controls The drug double gel loaded with levodopa, carbidopa, and entacapone prepared in Example 4 was used as the experimental group, and the commercially available entacapone double dopamine tablet II was used as the control group. A two-step in vitro simulated gastrointestinal digestion model was used to evaluate the concentration changes and release behavior of levodopa, carbidopa, and entacapone in different formulations during the simulated digestion process.

[0141] 5.2 Simulated gastric digestion stage The drug double gel sample was mixed with twice the volume of simulated gastric fluid. The simulated gastric fluid had a pepsin concentration of 5 mg / mL and a pH of 2.0.

[0142] The mixture was placed in a shaker at 37°C and incubated for 2 hours to simulate gastric digestion at 50 rpm. Samples were taken at predetermined time points to determine the concentrations of levodopa, carbidopa, and entacapone in the simulated gastric digestion medium.

[0143] The control group, commercially available entacapone and dopamine tablets II, was treated under the same simulated gastric digestion conditions.

[0144] 5.3 Conversion between simulated gastric juice digestion stage and simulated intestinal juice digestion stage After 2 hours of simulated gastric digestion, the pH of the digestion system was adjusted to 7.0, and the enzymes were inactivated at 95°C. Subsequently, an equal volume of simulated intestinal fluid was added to the system to initiate the simulated intestinal digestion stage.

[0145] 5.4 Simulated intestinal digestion stage The simulated intestinal fluid contained pancreatic enzymes at a concentration of 15 mg / mL, bile salts at a concentration of 10 mg / mL, and a pH of 7.0.

[0146] The system was placed in a shaker at 37°C and incubated for 2 hours at a speed of 100 rpm to simulate intestinal digestion. Samples were taken at predetermined time points.

[0147] It should be noted that the simulated intestinal digestion stage is recalculated from the start of intestinal digestion as 0 minutes, i.e. Figure 2 The 0–120 min values ​​represent the independent timing of the simulated intestinal digestion phase, rather than the cumulative time of the entire gastrointestinal digestion experiment.

[0148] 5.5 Drug Content Detection The concentrations of levodopa, carbidopa, and entacapone in the digestion medium at each sampling time point were determined by UPLC-MS / MS liquid chromatography-tandem mass spectrometry. Concentration-time curves were plotted with digestion time as the x-axis and drug concentration in the digestion medium as the y-axis.

[0149] The test results for the simulated gastric digestion stage are shown below. Figure 1 The test results for the simulated intestinal digestion stage are shown in [the image]. Figure 2 .

[0150] 5.6 Test Results like Figure 1 As shown in Figure A, during the simulated gastric digestion stage, the levodopa in the commercially available entacapone dopamine tablets II group was rapidly released in the early stage of digestion, reaching a high media concentration in about 20 to 40 minutes. In contrast, the levodopa in the dual gel group of the present invention had a significantly lower media concentration in the early stage of digestion, which gradually increased with the extension of digestion time, and reached the highest detectable concentration in this gastric digestion stage at 120 minutes.

[0151] The above results indicate that, compared with commercially available tablets, the drug dual gel of the present invention can reduce the rapid release of levodopa in the early stage of simulated gastric digestion, resulting in a slower release process of levodopa during the simulated gastric digestion stage.

[0152] like Figure 1 As shown in Figure B, there are differences in the concentration-time variation trends of carbidopa in the dual-gel group and the commercially available tablet group of the present invention, indicating that the dual-gel system can change the release behavior of carbidopa in the simulated gastric digestion process.

[0153] like Figure 1 As shown in Figure C, during the simulated gastric digestion stage, the mediator concentration of entacapone in the commercially available tablet group rapidly increased and remained at a high level, while the mediator concentration of entacapone in the dual-gel group of the present invention was significantly lower than that in the commercially available tablet group, indicating that the release behavior of entacapone in the dual-gel system is significantly different from that of ordinary tablets.

[0154] 5.7 Results of the simulated intestinal digestion stage like Figure 2 As shown in Figure A, after entering the simulated intestinal fluid digestion stage, the mediator concentration of levodopa in the commercially available tablet group rapidly decreased and further decreased to a low level during subsequent digestion; in contrast, the dual-gel group of the present invention was able to maintain a detectable levodopa concentration during the simulated intestinal fluid digestion process.

[0155] The above results further demonstrate that the dual-gel system of the present invention can alter the release behavior of levodopa during continuous simulated digestion in the gastrointestinal tract.

[0156] like Figure 2 As shown in B, the carbidopa concentrations in both groups decreased after entering the simulated intestinal digestion stage. However, the dual-gel group of the present invention maintained a certain carbidopa detection concentration during the subsequent simulated intestinal digestion process, while the carbidopa concentration in the commercially available tablet group remained at a low level.

[0157] like Figure 2 As shown in Figure C, during the simulated intestinal digestion stage, the medium concentration of entacapone in the commercially available tablet group remained at a high level, while the overall concentration of entacapone in the dual-gel group of the present invention was lower than that in the commercially available tablet group, further indicating that the dual-gel system can change the release behavior of entacapone in the simulated gastrointestinal environment.

Claims

1. A dual-gel drug for treating Parkinson's disease, characterized in that, The dual gel comprises an oleogel phase and a hydrogel phase; The oleogel phase includes camellia oil, white beeswax and entacapone, wherein, based on the oleogel phase, the mass fraction of white beeswax is 4% to 6%, and the entacapone is dispersed in the oleogel phase; The hydrogel phase includes pseudophyte seed gum, xanthan gum, levodopa and carbidopa, wherein, based on the hydrogel phase, the mass fraction of pseudophyte seed gum is 0.4%, the mass fraction of xanthan gum is 1.0% to 1.5%, and the levodopa and carbidopa are loaded in the hydrogel phase; The oleogel phase is dispersed in the hydrogel phase to form an oil-in-water bigel.

2. The dual-gel treatment for Parkinson's disease according to claim 1, characterized in that, The volume ratio of the hydrogel phase to the olegel phase is 1:

1.

3. The dual-gel treatment for Parkinson's disease according to claim 2, characterized in that, The xanthan gum has a mass fraction of 1.5%, and the white beeswax has a mass fraction of 6%.

4. The dual-gel treatment for Parkinson's disease according to claim 1, characterized in that, The mass ratio of L-DOPA, Carbidopa, and Entacarbon is 4:1:

8.

5. The Parkinson's disease treatment drug dual gel according to claim 3, characterized in that, The oleogel phase is dispersed in the hydrogel phase in the form of oil droplets, forming an oil-in-water dual gel; the oil droplets include oil droplets with a particle size of 2 to 5 μm and oil droplets with a particle size greater than 100 μm.

6. The Parkinson's disease treatment drug dual gel according to claim 3, characterized in that, Under conditions of 25℃, 1.0% fixed strain, and a frequency scanning of 0.1–10 Hz, the storage modulus G' of the dual gel is greater than the loss modulus G'', and the loss factor tanδ is 0.1–1.

7. A method for preparing a dual-gel for treating Parkinson's disease as described in claim 1, characterized in that, Includes the following steps: S1. Add levodopa and carbidopa to the crude extract of pseudophys seed gum, mix, add xanthan gum, and heat and stir to obtain a hydrogel phase loaded with levodopa and carbidopa. S2. Entacapone is dispersed in camellia oil, then white beeswax is added and heated to melt the white beeswax, to obtain an oleogel phase loaded with entacapone. S3. The hydrogel phase and olegel phase are mixed under heat preservation and subjected to high-speed shearing, followed by cooling and solidification to obtain the Parkinson's disease treatment drug dual gel.

8. The preparation method according to claim 7, characterized in that, The preparation method of the crude extract of false sorrel seed gum includes: mixing false sorrel seeds with deionized water at a mass-volume ratio of 1:10, extracting in a water bath at 80°C, filtering to remove the false sorrel seeds, and obtaining the crude extract of false sorrel seed gum.

9. The preparation method according to claim 7, characterized in that, In step S1, levodopa and carbidopa are added to the crude extract of pseudoalgae seed gum at 60°C; in step S2, entacapone is added to camellia oil at 60°C for dispersion, and white beeswax is added and heated to melt the white beeswax; in step S3, the hydrogel phase and olegel phase are mixed at a volume ratio of 1:1 and intermittently sheared at a speed of 10000 r / min, with a 20-second pause after every 1 minute of shearing, for a total shearing time of 5 minutes; after shearing, the mixture is allowed to stand and solidify at 4°C for 24 hours.

10. The use of the Parkinson's disease treatment drug dual gel according to claim 1 in the preparation of a Parkinson's disease treatment drug for oral administration to patients with Parkinson's disease accompanied by dysphagia.

Images