Osmotic pump tablet, method for preparing same, and use thereof

Abstract

Provided are an osmotic pump tablet, a method for preparing same, and use thereof. The osmotic pump tablet comprises a tablet core and a coating film enclosing the tablet core. The coating film is provided with a drug release hole. The tablet core comprises a drug-containing layer. The drug-containing layer comprises an active pharmaceutical ingredient, a hydrophilic polymer, and a surfactant, the hydrophilic polymer comprises hydroxypropyl cellulose, and the surfactant comprises poloxamer. Alternatively, the drug-containing layer comprises an active pharmaceutical ingredient and a hydrophilic polymer, but does not comprise a surfactant, and the hydrophilic polymer comprises povidone K29 / 32. Alternatively, the osmotic pump tablet comprises a drug-containing quick-release outer coating, the drug-containing quick-release outer coating comprises an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient is a binder.

Description

Osmotic pump tablet, preparation method and application thereof

[0001] This application claims priority to Chinese patent application No. 2024100656387, filed on January 16, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present disclosure relates to an osmotic pump tablet, a preparation method thereof, and applications thereof. Background Art

[0003] Many active pharmaceutical ingredients (APIs), including levodopa (LD), carbidopa (CD), baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin, have a restricted absorption window in the upper gastrointestinal tract. Incorporating these APIs into conventional sustained-release dosage forms not only results in reduced bioavailability but also prevents the achievement of extended therapeutic coverage. Therefore, numerous techniques have been developed in the prior art to extend their gastric residence time. These techniques are: dilation (USP 4,735,804, 5,002,772, and 6,685,962), inflation (USP 4,434,153, 5,750,585, 5,972,389, 6,120,803, 6,660,300 Bl, US2007 / 0196396 Al, and USP 9,439,851), flotation (USP 4,167,558, 5,232,704, and 6,261,601), raft formation (USP 4,140,760, and 5,068,109), sinking (USP 4,193,985, and 4,900,557), and mucoadhesion (USP 6,207,197, and US2005 / 030552). The success of these technologies has been very limited, particularly when oral dosage forms using these technologies are administered in the fasting state. Therefore, there is a need for a new controlled-release system, or controlled-drug release system, that can provide prolonged exposure to the active ingredients of these drugs, with their absorption window restricted to the upper gastrointestinal tract. Combining an oral retention device with these drugs to form a drug-device combination, forming an oral retention drug delivery system, can provide prolonged exposure to these drugs with an absorption window restricted to the upper gastrointestinal tract.

[0004] Furthermore, for topical administration to the oral mucosa, commonly used liquid or semisolid formulations such as sprays, gargles, and ointments have a short residence time in the oral cavity and cannot achieve sustained drug delivery. Therefore, a drug delivery system that can provide prolonged exposure to drug ingredients is needed, suitable for drugs with an absorption window in the upper gastrointestinal tract or that require topical oral administration. A drug delivery device is loaded with the drug and, after being combined with a retainer, fixed in the oral cavity to form a controlled-release drug system, providing prolonged exposure to drugs with an absorption window limited to the upper gastrointestinal tract.

[0005] Regarding oral drug delivery devices, patent applications US10668274 and CN1997421A disclose an oral drug-containing container based on an electrically controlled drug release mechanism. The drug-containing container and electrically controlled system claimed in the patents are difficult to implement. CN105873631A discloses an oral drug delivery device that requires an electronic pump or a mechanical pump as an external power source to achieve drug delivery. In addition, CN1925823A discloses a tooth bracket for attaching fluoride pellets to teeth to improve the treatment or prevention of dental caries. This patent application does not involve drug absorption in the upper gastrointestinal tract. In addition, patent application CN109908461A discloses an oral drug delivery device for dentures, braces, or oral implants, which is suitable for oral mucosal drug delivery and does not involve drug absorption in the upper gastrointestinal tract. The above-mentioned published patent applications either require external power, or need to rely on dentures, braces, etc. to achieve delivery, or do not involve drug absorption at the absorption end in the upper gastrointestinal tract.

[0006] CN114191307A and CN212973560U disclose an oral retention device for retaining tablets in the oral cavity, providing long-term exposure of drugs with absorption windows limited to the upper gastrointestinal tract, so as to obtain long-term stable blood drug concentrations. The oral retention device takes into account that the tablet is inserted from the back to the front, close to the throat and blocked by oral tissues such as the buccal fat pad tip, so that the tablet is not easy to fall off when the device is worn. At the same time, the tooth-fitting components in the oral retention device can fit the patient's teeth according to the personalized design, making it stable to wear. However, for patients with clinically short crowns, small buccal space or special oral conditions, when the oral movement amplitude is large, the oral retention device may be poorly retained and there is a risk of tilting or falling off.

[0007] The above-mentioned intraoral drug delivery devices do not take into account the wearing firmness under special oral conditions, and the complex structure or large device volume may cause poor wearing comfort and safety for patients, and will also have a great impact on facial appearance when worn.

[0008] Osmotic pump tablets are an ideal oral controlled-release formulation for active pharmaceutical ingredients whose absorption window is limited to the upper gastrointestinal tract. Early osmotic pump tablets were single-layer tablets, typically consisting of a water-soluble drug core, a coating, and drug release pores. When exposed to an aqueous environment, water enters the tablet core through the semipermeable controlled-release membrane, hydrating the core to form a drug solution, which in turn creates an osmotic pressure differential between the tablet core and the outside. Driven by this osmotic pressure differential, water continuously enters the tablet core through the semipermeable coating, driving the drug solution out through the drug release pores. Single-layer osmotic pump tablets are suitable for controlled-release formulations of high-dose water-soluble APIs. However, for poorly water-soluble drugs, the drug itself generates low osmotic pressure. While adding an osmotic agent can increase osmotic pressure, the solid drug powder tends to settle downward, making it difficult to achieve an ideal high-dose osmotic pump tablet for poorly water-soluble drugs using single-layer tablets. Drug release is non-constant, and high residual drug content is likely.

[0009] Compared with single-layer core osmotic pump tablets, double-layer core osmotic pump tablets are composed of a drug-containing layer and a push layer. They can provide zero-order constant-rate drug release for both water-soluble and poorly water-soluble drugs, and the drug release is complete (drug release is greater than 90%). Double-layer core osmotic pump tablets are currently the most mature and suitable dosage form for industrial production of drugs, especially poorly water-soluble drugs. However, the drug release amount is limited by the drug loading and the permeability of the controlled release membrane, and its drug loading and release amount are often not high. Conventional double-layer core osmotic pump tablets cannot maintain the interface between the drug-containing layer and the push layer due to the limitations of their own structure when pushing drugs, especially large doses of drugs. As a result, in the middle and late stages of drug release, the push layer passes through the drug release hole before the drug in the drug-containing layer, changing the drug release rate and resulting in a large amount of drug residue.

[0010] Another type is high-dose osmotic pump tablets, which, in order to achieve high-flux drug release, pose a significant challenge to the physical and chemical properties of the controlled-release membrane. On the one hand, the membrane needs to possess high mechanical strength to withstand the resistance caused by the passage of high-drug-loaded drug slurry through the release pores, thereby preventing membrane rupture during the drug release process. At the same time, the membrane needs to have good medium permeability to allow water to quickly pass through the controlled-release membrane into the tablet core, allowing the drug to be rapidly released after hydration of the drug-containing layer. Currently, there are no high-dose osmotic pump tablets suitable for active ingredients with an absorption window limited to the upper gastrointestinal tract, and this problem needs to be urgently addressed. Summary of the Invention

[0011] To overcome the inability of current controlled-release drugs to provide a long-term, stable plasma profile of active pharmaceutical ingredients, and to avoid cellulose acetate precipitation during the coating process of the rate-controlling membrane, thereby solving the defects of uneven coating and unstable drug release, a controlled-release system for active pharmaceutical ingredients and a preparation method thereof are provided.

[0012] Therefore, one aspect of the present disclosure relates to a controlled-release dosage form having an absorption window in the upper gastrointestinal tract, the controlled-release dosage form comprising a controlled-release platform and a retention platform;

[0013] The controlled release platform (ERP) is a pharmaceutical composition comprising a tablet core and a coating film, wherein the tablet core comprises a drug-containing layer, and the coating film comprises cellulose acetate and copovidone, wherein the weight of the cellulose acetate is 50-70% of the weight of the coating film; and the weight of the copovidone is 30-50% of the weight of the coating film.

[0014] The retention platform functions to retain the controlled-release platform in the oral cavity. At least one end of the retention platform is connected to a cover body, which enables the controlled-release platform to be retained in the retention platform.

[0015] To address the technical problem of low bioavailability due to the short gastric residence time of active pharmaceutical ingredients, the present disclosure relates, in another aspect, to a novel oral retention device that retains tablets in the oral cavity and prevents them from falling out. Specifically, the present disclosure provides an oral retention device that allows tablets to be inserted from back to front. Because the back of the device is closer to the throat and blocked by oral tissue such as the buccal fat pad tip and the pterygomandibular fold, the tablet is retained in the oral retention device, preventing suffocation due to accidental swallowing.

[0016] The oral retention device is similar to the above-mentioned retention platform, but does not include a cover body. It includes a tooth-accepting component and a drug-carrying component, wherein the tooth-accepting component is connected to the drug-carrying component, wherein the tooth-accepting component is used to bridge the teeth in the oral cavity and match the teeth, and the drug-carrying component can accommodate at least one tablet and is used to retain the tablet in the oral cavity.

[0017] In some embodiments, the tablet in the oral retention device can be a retention platform or pharmaceutical composition or osmotic pump tablet in the present disclosure.

[0018] In some embodiments, the copovidone is prepared by the following method, comprising the steps of polymerizing vinyl pyrrolidone and vinyl acetate, wherein the weight ratio of the vinyl pyrrolidone to the vinyl acetate is 40:60-80:20. Preferably, the weight ratio of the vinyl pyrrolidone to the vinyl acetate is 50:50-70:30. More preferably, the weight ratio of the vinyl pyrrolidone to the vinyl acetate is 60:40.

[0019] In some embodiments, the retention platform comprises a customized retention component and a drug retention component, wherein the drug retention component is capable of securing the controlled-release platform, and the customized retention component is capable of maintaining the drug retention component in the oral cavity. More preferably, the drug retention component comprises one or more reservoirs. In one embodiment, the reservoirs are basket-shaped. In another embodiment, the cross-section of the reservoirs is polygonal, a closed circular loop, an open circular loop, or a combination thereof.

[0020] In some embodiments, at least one end of the reservoir is connected to a cover, which enables the controlled-release platform to be retained in the reservoir; more preferably, the cover is a strip.

[0021] In some embodiments, the retention component can be adapted to fit any one or more teeth in the oral cavity. Preferably, the permanent teeth are mandibular. More preferably, the molars are mandibular. Most preferably, the mandibular second molar and its anterior and posterior molars are mandibular.

[0022] The retention component can be customized to fit, wrap, snap in or insert the entire maxillary teeth or the entire mandibular permanent teeth; preferably, wrap, snap in or insert the mandibular permanent teeth; more preferably, wrap the mandibular molars; most preferably, wrap, snap in or insert the mandibular second molar and its adjacent first molar and part of the second bicuspid.

[0023] When the retention platform is referred to as an oral retention device, the personalized retention component may be a tooth-fitting component, and the drug fixing component may be referred to as a drug-carrying component.

[0024] In some embodiments, the tooth engaging component and the drug carrying component are connected at their respective sides.

[0025] In some embodiments, the tooth-engaging member can be adapted to engage with any one or more teeth in the oral cavity.

[0026] In some embodiments, the tooth engaging member has a length of 2-5 teeth.

[0027] In some embodiments, the teeth are mandibular permanent teeth, preferably mandibular molars, and more preferably any combination of: (i) mandibular first molars and second molars; (ii) first molars, second molars and second premolars; (iii) first molars, second molars and third molars; or (iv) first molars, second molars, third molars and second premolars.

[0028] In some embodiments, the tooth engaging member wraps around, fits into, snaps into, or inserts into the tooth to which it is engaged.

[0029] In some embodiments, the drug carrying member is a mesh structure or a non-mesh structure.

[0030] In some embodiments, the cross-section of the drug carrying member is circular, elliptical, polygonal, or a special-shaped closed or open ring structure.

[0031] In some embodiments, the drug carrying component includes at least one ring body and at least one limiting member, or the drug carrying component is composed of at least one limiting member; wherein, the ring body has an opening for inserting tablets, and the structure of the limiting member is used to confine the tablets in the drug carrying component.

[0032] In some embodiments, the ring is an open ring or a closed ring.

[0033] In some embodiments, the ring body is a closed ring body or an open ring body that is circular, elliptical, polygonal or irregular in shape.

[0034] In some embodiments, the number of the ring body is one, and the ring body is located on the molar side in the horizontal direction formed by the molars and the incisors.

[0035] In some embodiments, the limiting member is in an arc-shaped hollow or solid shape.

[0036] In some embodiments, the limiting member is formed by connecting a closed loop body and a semicircle perpendicular to the closed loop body.

[0037] In some embodiments, the limiting member is adjacent to the ring body, or the limiting member is spaced apart from the ring body. Preferably, the adjacent member is integrally formed, or connected together via a connecting structure.

[0038] In some embodiments, the number of the limiting member is one.

[0039] In some embodiments, the limiting member is located on the side of the incisors in the horizontal direction formed by the molars and the incisors.

[0040] In some embodiments, the opening is oriented toward the molars in the horizontal direction formed by the molars and the incisors, so that the tablet can be inserted from the molars toward the incisors in the horizontal direction; or, the opening is arranged perpendicular to the horizontal direction, and the tablet is inserted from top to bottom perpendicular to the horizontal direction; or, the opening is oriented toward the buccal side perpendicular to the horizontal direction, and the tablet is inserted from the buccal side to the lingual side perpendicular to the horizontal direction.

[0041] The controlled release platform of the present disclosure is an osmotic pump delivery system comprising LD and CD. The osmotic pump delivery system can be a single-layer basic osmotic pump or a double-layer push-pull system. The osmotic pump delivery system can provide constant release of LD / CD in the oral cavity, which is in sharp contrast to the matrix extended release system (matrix extended release system). The matrix extended release system is sensitive to the conditions in the oral cavity, such as pH, saliva availability, and hydrated matrix tablets through the voluntary or involuntary friction of the tongue.

[0042] The retention enabling platform (REP) disclosed herein is a customized ERP retainer that secures the ERP in the oral cavity. Thus, the LD / CD can be released near the throat and easily absorbed into the stomach. This REP has safety features that prevent accidental blockage of the controlled-release system. In this disclosure, "customization" refers to the preparation of a retention platform or retention assembly that can secure the ERP in the oral cavity and conform to the shape of one or more teeth, or the entire maxillary or mandibular teeth of the patient, based on the shape of the patient's teeth.

[0043] Another aspect of the present disclosure relates to a method for preparing the controlled-release dosage form. The retention platform or oral retention device can be prepared by 3D printing, injection molding, or impression molding. Combining oral scanning, CAD / CAM design, and preparation methods can accurately and rapidly generate REPs based on individual oral scan images.

[0044] 3D printing works on essentially the same principle as conventional printers, differing only in the materials used. Conventional printers use ink and paper, while 3D printers are loaded with various "printing materials," such as metal, ceramic, plastic, and sand. Once connected to a computer, the printer is controlled by the computer to build up layers of these materials, ultimately transforming the computer blueprint into a physical object. 3D printing mirrors the technical principles of conventional printers, with the layered processing process being very similar to inkjet printing. This type of printing technology is known as 3D printing. There are many different 3D printing technologies, differing in the way they utilize available materials and the layer-by-layer construction used to create parts. Common materials used in 3D printing include nylon fiberglass, polylactic acid, ABS resin, durable nylon, plaster, aluminum, titanium, titanium alloys, stainless steel, silver plating, gold plating, cobalt-chromium alloys, cobalt-chromium-molybdenum alloys, and rubber. The advantages of 3D printing include automated operation, rapid production speeds, and the direct and precise conversion of computer blueprints into physical models. It is also suitable for small-scale custom manufacturing.

[0045] The 3D printing process includes the following steps:

[0046] (1) In the design software, preferably 3Shape Dental System, add the saved drug-carrying component design and assemble it with the tooth-engaging component design to form an integrated oral retention device design, and export the file for 3D printing;

[0047] (2) importing the 3D printable file into a 3D printer and printing the oral retention device; the 3D printing preferably uses a laser sintering process;

[0048] Preferably, before step (1), the method further includes: (0) designing and saving a plan for a drug-carrying component based on tablet size data in software preferably SolidWorks; and / or, designing a plan for a tooth-matching component based on the subject's tooth size data in design software 3Shape Dental System;

[0049] More preferably, the tablet size data and / or the subject's teeth data are obtained by scanning using a scanner, preferably a 3Shape scanner. Scanner or Medit i500 scanner.

[0050] In some embodiments, using "3Shape The intraoral scanner scans the tablet's dimensional data, then imports the data into the "SolidWorks" software to design a solution for the drug-carrying component that can hold the drug part, and creates and saves the solution as a "standard attachment" file; using "3Shape The subject's teeth are scanned using an intraoral scanner, and the data is imported into the "3Shape Dental System" software. A dental anastomotic component is designed based on the dental data. In the "3Shape Dental System" software, "standard accessories" are added and assembled with the dental anastomotic component to form an integrated oral retention device. A 3D printable file is then exported. The 3D printable file is imported into a 3D printer and the oral retention device is printed. The 3D printing preferably uses a laser sintering process.

[0051] Injection molding, also known as injection molding, is a combined injection and molding process. This involves stirring a completely molten polymer material through a screw at a certain temperature, injecting it into a mold cavity at high pressure, and then cooling and solidifying it to produce a molded product. This method is suitable for the mass production of complex-shaped parts and is a key processing method. The advantages of injection molding include high production speed, high efficiency, automated operation, a wide variety of designs and shapes, from simple to complex, and from large to small. Furthermore, the product can be precisely dimensioned, easily updated, and can be produced into complex-shaped parts. Injection molding is suitable for mass production and the molding of complex-shaped products.

[0052] Wherein, the injection molding comprises the following steps:

[0053] (1) preparing a tooth anastomotic component model based on the tooth model;

[0054] (2) preparing a drug-carrying component model according to the tablet size;

[0055] (3) obtaining an oral retention device model integrating a tooth-engaging component and a drug-carrying component;

[0056] (4) Prepare personalized oral retention devices through traditional injection molding process;

[0057] In some embodiments, the dental model is prepared by traditional impression taking technology or by obtaining the subject's dental data through oral scanning technology and printing.

[0058] In some embodiments, the material of the tooth anastomotic component model, the drug-carrying component model and the oral retention device model is dental wax, and / or the material of the tooth model is plaster or resin.

[0059] Impression molding, first prepare a drug fixing component that is suitable for the controlled release platform. Secondly, process the oval thermoplastic sheet through conventional technology. Finally, prepare the preparation of personalized REP, heat a thermoplastic sheet in hot water at about 70°C to soften it and have good plasticity. When the thermoplastic sheet becomes translucent (about 1 minute), take it out and place it on the teeth, press the softened thermoplastic sheet so that it completely wraps the teeth to form a retention component that fits the teeth perfectly. Then quickly embed the drug fixing component into the uncured retention component, cool and solidify it into a personalized retention platform (REP). You can spray some water briefly to further accelerate the cooling, wait for the personalized retention platform to cool and restore its original opaque hard sheet state, and remove the cooled personalized retention platform from the mouth.

[0060] In some embodiments, the method of preparing the oral retention device of the present disclosure is impression molding, which comprises:

[0061] The drug-carrying component is designed according to the size of the tablet; the tooth-fitting component is prepared with polycaprolactone (PCL) as the material, and the drug-carrying component is prepared with cobalt-chromium alloy as the material; the tooth-fitting component and the drug-carrying component are assembled into a complete oral retention device.

[0062] In some embodiments, a drug-carrying component capable of loading an osmotic pump tablet is first prepared using a conventional injection molding process; the thermoplastic sheet is then heated and softened to form a tooth-fitting component, and the softened tooth-fitting component is then interlocked with the drug-carrying component. After cooling, an integrated oral retention device is formed and removed from the oral cavity.

[0063] In some embodiments, the retention platform or oral retention device is made from one or more mouth-stable materials including mouth-stable metals and thermoplastic elastomers.

[0064] In some embodiments, the mouth-stable metal includes or is selected from dental titanium, stainless steel, cobalt-chromium alloy, cobalt-chromium-molybdenum alloy, nickel-chromium alloy or precious metal, and the thermoplastic elastomer includes polycaprolactone (PCL), ethylene-vinyl acetate copolymer (EVA), high-density polyethylene (HDPE), polypropylene (PP), polyacrylate, polyurethane, silicone polymer, polyester, poly(styrene-ethylene-butylene-styrene) ("SEBS"), poly(styrene-butadiene-styrene) ("SBS"), poly(styrene-isoprene-styrene) ("SIS"), or copolymers of any two or more thereof, or physical combinations thereof.

[0065] In some embodiments, the tooth engaging component and the drug carrying component are made of cobalt-chromium alloy.

[0066] The pharmaceutical composition or upper gastrointestinal tract (UGI) controlled-release drug delivery system disclosed herein includes single-layer basic osmotic pumps, double-layer push-pull osmotic pumps, and double-layer push-pull osmotic pumps with a rapid-release drug outer coating, but is different from the osmotic pumps in the prior art.

[0067] In the controlled-release dosage form disclosed above, preferably, in the controlled-release platform, the drug-containing layer contains pharmaceutically active ingredients and excipients.

[0068] In some embodiments, the pharmaceutically active ingredient is one or more of levodopa or its ester or salt, carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin; or one or both of levodopa or its ester and carbidopa. The ester of levodopa may be a levodopa alkyl ester or a deuterated levodopa alkyl ester, such as levodopa methyl hydrochloride. The salt of levodopa may be levodopa ethyl ester hydrochloride. The pharmaceutically active ingredient is, for example, selected from antifungal drugs and antitumor drugs. The antifungal drug is, for example, selected from one or more of nystatin, fluconazole, posaconazole, isavuconazole, voriconazole, anidulafungin, caspofungin, and micafungin. The antitumor drug is, for example, selected from one or more of 5-fluorouracil, paclitaxel, and capecitabine.

[0069] In some embodiments, the pharmaceutically active ingredient comprises levodopa and / or carbidopa.

[0070] In some embodiments, the excipient is one or more of a filler, an osmotic agent, a hydrophilic polymer, a binder, a lubricant, a preservative, a flavoring agent, an acidulant, and an antioxidant. More preferably, the excipient is one or more of a filler, an osmotic agent, a hydrophilic polymer, a binder, a lubricant, and a preservative. Even more preferably, the excipient is a filler, an osmotic agent, a hydrophilic polymer, a binder, a lubricant, and a preservative.

[0071] In one embodiment, when the pharmaceutical active ingredient comprises levodopa, the content of levodopa is 20-70 wt % based on the total weight of the drug-containing layer. In another embodiment, when the pharmaceutical active ingredient comprises carbidopa, the content of carbidopa is 0-20 wt % but not 0 wt % based on the total weight of the drug-containing layer.

[0072] In one embodiment, the pharmaceutically active ingredient comprises levodopa, and the content of levodopa is 30-50 wt % based on the total weight of the drug-containing layer. In another embodiment, the pharmaceutically active ingredient comprises carbidopa, and the content of carbidopa is 1-10 wt % based on the total weight of the drug-containing layer.

[0073] Preferably, in the drug-containing layer, when the excipient contains a filler, the filler is one or more of microcrystalline cellulose, hydroxypropyl cellulose, and mannitol. Based on the total weight of the drug-containing layer, the content of the filler is preferably 0-50 wt% but not 0%.

[0074] In another embodiment, when the excipient contains an osmotic agent, the osmotic agent is one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, and glucose. The content of the osmotic agent is preferably 0-50 wt % but not 0 wt % based on the total weight of the drug-containing layer.

[0075] In another embodiment, when the excipient contains a hydrophilic polymer, the hydrophilic polymer is one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone (e.g., povidone K30 or povidone K29 / 32, preferably povidone K29 / 32), and hydroxyethyl cellulose. The content of the hydrophilic polymer is preferably 0-50 wt % but not 0 wt % based on the total weight of the drug-containing layer.

[0076] In another embodiment, when the excipient contains an acidulant, the acidulant is one or more of citric acid, sodium citrate, potassium citrate, malic acid, fumaric acid, lactic acid, phosphoric acid, and tartaric acid. The content of the acidulant is preferably 0-10 wt % but not 0 wt % based on the total weight of the drug-containing layer.

[0077] Preferably, the pharmaceutical composition further comprises an osmotic push layer. The osmotic push layer preferably comprises a hydrophilic polymer, an osmotic agent, and a binder, and optionally a lubricant and / or a colorant. The osmotic push layer and the drug-containing layer are components of a bilayer tablet core, and the coating film is wrapped around the exterior of the tablet core. The pharmaceutical composition can be a type of osmotic pump controlled-release drug delivery system, i.e., a bilayer push-pull osmotic pump.

[0078] For pharmaceutical compositions in double-layer push-pull osmotic pumps, the hydrophilic polymer in the osmotic push layer is preferably kappa-carrageenan, sodium carboxymethylcellulose, or polyethylene oxide. The molecular weight of the hydrophilic polymer is preferably 75,000-7,500,000. The content of the hydrophilic polymer is preferably 25-85 wt % based on the total weight of the osmotic push layer.

[0079] In one embodiment, the osmotic agent in the push layer of the osmotic pump is one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, and glucose. The content of the osmotic agent is preferably 5-65 wt % based on the total weight of the osmotic push layer.

[0080] In another embodiment, the binder in the osmotic pump push layer is one or more of methylcellulose, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone and gelatin. The content of the binder is preferably 3-20 wt % based on the total weight of the osmotic push layer.

[0081] In another embodiment, when the osmotic pump push layer contains a lubricant, the lubricant is one or more of magnesium stearate, magnesium fumarate stearate, talc, and colloidal silicon dioxide. The weight percentage of the lubricant, based on the total weight of the osmotic push layer, is preferably 0-2 wt % but not 0%.

[0082] In another embodiment, when the osmotic push layer contains a colorant, the colorant is one or more of red iron oxide, yellow iron oxide, and black iron oxide. The weight percentage of the colorant is 0-5 wt% but not 0% based on the total weight of the osmotic push layer.

[0083] Preferably, the osmotic push layer comprises sodium carboxymethylcellulose, sorbitol, povidone, red iron oxide, and magnesium stearate; or comprises sodium carboxymethylcellulose, hydroxypropyl cellulose, sorbitol, red iron oxide, and magnesium stearate; preferably, is composed of sodium carboxymethylcellulose, povidone K30, sorbitol, red iron oxide, and magnesium stearate; or is composed of sodium carboxymethylcellulose, hydroxypropyl cellulose, sorbitol, red iron oxide, and magnesium stearate. More preferably, the sodium carboxymethylcellulose is sodium carboxymethylcellulose 7H4XF or 9H4XF.

[0084] In one embodiment, based on the total weight of the osmotic push layer, the osmotic push layer contains 25-85wt% of sodium carboxymethyl cellulose, 5-65wt% of sorbitol, 3-20wt% of povidone, 0-5wt% of red iron oxide and 0.5-2wt% of magnesium stearate; or contains 25-85wt% of sodium carboxymethyl cellulose, 5-65wt% of sorbitol, 3-20wt% of hydroxypropyl cellulose, 0-5wt% of red iron oxide and 0.5-2wt% of magnesium stearate.

[0085] In another embodiment, based on the total weight of the osmotic push layer, the osmotic push layer contains 55 wt% of sodium carboxymethyl cellulose, 39.0 wt% of sorbitol, 5.0 wt% of povidone, 0.5 wt% of red iron oxide and 0.5 wt% of magnesium stearate.

[0086] In another embodiment, based on the total weight of the osmotic push layer, the osmotic push layer contains 55 wt% of sodium carboxymethyl cellulose, 34.0 wt% of sorbitol, 10.0 wt% of povidone K30, 0.5 wt% of red iron oxide and 0.5 wt% of magnesium stearate.

[0087] In another embodiment, the osmotic push layer contains 55 wt% of sodium carboxymethylcellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose, 0.5 wt% of red iron oxide and 0.5 wt% of magnesium stearate, based on the total weight of the osmotic push layer.

[0088] In another embodiment, the osmotic push layer contains 49.0 wt% of sodium carboxymethyl cellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of red iron oxide and 0.5 wt% of magnesium stearate, based on the total weight of the osmotic push layer.

[0089] In some preferred embodiments, the pharmaceutical composition has a layer of drug-containing rapid-release outer coating outside the coating film, thereby forming a three-layer structure with the inner layer being the tablet core, the middle layer being the coating film, and the outer layer being the outer coating.

[0090] More preferably, the drug-containing rapid-release outer coating comprises a pharmaceutically active ingredient and excipients, wherein the pharmaceutically active ingredient comprises levodopa and / or carbidopa, and the excipients are one or more of hydroxypropyl cellulose, aspartame, and mint flavor.

[0091] In one embodiment, based on the total weight of the drug-containing rapid-release outer coating, when the active pharmaceutical ingredient is levodopa, the content of levodopa is 0-75wt% but not 0%, preferably 23.78-75wt%. When the active pharmaceutical ingredient is carbidopa, the content of carbidopa is 0-93wt% but not 0%, preferably 26.85wt%-93wt%. When the excipient of the outer coating contains hydroxypropyl cellulose, the content of hydroxypropyl cellulose is 2-20wt%, preferably 10wt%. When the excipient of the outer coating contains aspartame, the content of aspartame is 0-5wt%, preferably 0.9-5wt%. When the excipient of the outer coating contains mint essence, the content of mint essence is 0-5wt%, preferably 0.1wt%.

[0092] More preferably, the coating comprises no less than 2.0% of the tablet core weight. The coating comprises one or more openings, preferably with diameters of 0.5 mm to 1.0 mm, more preferably 0.5 mm, 0.75 mm, and 1.0 mm. Preferably, the coating comprises 2.0 to 15.0% of the tablet core weight. More preferably, the coating comprises 4.0 to 8.0% of the tablet core weight.

[0093] Preferably, in one embodiment, the pharmaceutical composition comprises a drug-containing layer and a coating film. In another embodiment, the pharmaceutical composition comprises a drug-containing layer, an osmotic push layer, and a coating film. In another embodiment, the pharmaceutical composition comprises a drug-containing layer, an osmotic push layer, a coating film, and an outer coating.

[0094] Preferably, the drug-containing layer consists of levodopa, carbidopa, microcrystalline cellulose, mannitol, citric acid, hydroxypropyl methylcellulose and magnesium stearate. In another embodiment, the drug-containing layer consists of levodopa, microcrystalline cellulose, hydroxypropyl methylcellulose and magnesium stearate. In another embodiment, the drug-containing layer consists of levodopa, carbidopa, mannitol, citric acid and magnesium stearate. In another embodiment, the drug-containing layer consists of levodopa, carbidopa, hydroxypropyl cellulose, mannitol, citric acid and magnesium stearate. In another embodiment, the drug-containing layer consists of levodopa, carbidopa, hydroxypropyl cellulose, mannitol, citric acid and magnesium stearate. In another embodiment, the drug-containing layer consists of levodopa, carbidopa, hydroxypropyl cellulose, mannitol, citric acid and povidone K30. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropyl cellulose, mannitol, povidone K30, magnesium stearate, mint flavor and aspartame. In another embodiment, the drug-containing layer consists of levodopa, mannitol, povidone K30 and magnesium stearate. In another embodiment, the drug-containing layer consists of levodopa, carbidopa, hydroxypropylcellulose, mannitol, aspartame and magnesium stearate. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropylcellulose, mannitol, povidone K30, magnesium stearate, mint flavor and aspartame. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropylcellulose, mannitol, povidone K30, magnesium stearate and aspartame. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropylcellulose, mannitol, povidone K30, magnesium stearate and aspartame. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropylcellulose, mannitol, magnesium stearate, mint flavor and aspartame. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropylcellulose, povidone, mannitol and magnesium stearate.

[0095] Preferably, the osmotic push layer is composed of sodium carboxymethylcellulose, povidone, sorbitol, red iron oxide, and magnesium stearate, or is composed of sodium carboxymethylcellulose, hydroxypropyl cellulose, sorbitol, red iron oxide, and magnesium stearate. Preferably, the sodium carboxymethylcellulose is sodium carboxymethylcellulose 7H4XF or 9H4XF. The povidone is preferably povidone K30. The hydroxypropyl cellulose is hydroxypropyl cellulose EXF.

[0096] In one embodiment, the outer coating consists of levodopa, carbidopa, hydroxypropylcellulose, aspartame, and mint flavor; or consists of levodopa, carbidopa, hydroxypropylcellulose, and aspartame. In another embodiment, the outer coating consists of carbidopa, hydroxypropylcellulose, and aspartame. In another embodiment, the outer coating consists of levodopa, hydroxypropylcellulose, and mint flavor. It is well known to those skilled in the art that the phrase "comprising" can be replaced with "consisting of."

[0097] Preferably, based on the total weight of the drug-containing layer,

[0098] The drug-containing layer consists of 40 wt% levodopa, 10.8 wt% carbidopa, 20 wt% microcrystalline cellulose, 18.7 wt% mannitol, 5 wt% citric acid, 5 wt% sodium hydroxypropyl methylcellulose and 0.5 wt% magnesium stearate; or

[0099] The drug-containing layer consists of 38 wt% levodopa, 50 wt% microcrystalline cellulose, 10 wt% hydroxypropyl methylcellulose and 2 wt% magnesium stearate; or

[0100] The drug-containing layer consists of 19.5 wt% levodopa, 20 wt% carbidopa, 50 wt% mannitol, 10 wt% citric acid and 0.5 wt% magnesium stearate; or

[0101] The drug-containing layer is composed of 40 wt% levodopa, 10.8 wt% carbidopa, 31 wt% hydroxypropyl cellulose, 12.7 wt% mannitol, 5 wt% citric acid and 0.5 wt% magnesium stearate; or

[0102] The drug-containing layer is composed of 40 wt% levodopa, 10.8 wt% carbidopa, 31 wt% hydroxypropyl cellulose, 12.7 wt% mannitol, 5 wt% citric acid and 0.5 wt% povidone K30; or

[0103] The drug-containing layer is composed of 45wt% levodopa, 31wt% hydroxypropyl cellulose, 16wt% mannitol, 5wt% povidone K30, 1wt% magnesium stearate, 1wt% mint flavor and 1wt% aspartame; or

[0104] The drug-containing layer is composed of 70wt% levodopa, 9wt% mannitol, 20wt% povidone K30 and 1wt% magnesium stearate; or

[0105] The drug-containing layer consists of 20 wt% levodopa, 20 wt% carbidopa, 50 wt% hydroxypropyl cellulose, 4 wt% mannitol, 5 wt% aspartame and 1 wt% magnesium stearate; or

[0106] The drug-containing layer consists of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 17 wt% mannitol, 5 wt% povidone K30, 1 wt% magnesium stearate and 1 wt% aspartame; or

[0107] The drug-containing layer consists of 62.5 wt% levodopa, 31 wt% hydroxypropyl cellulose, 4.5 wt% mannitol, 1 wt% magnesium stearate, 0.1 wt% mint flavor and 0.9 wt% aspartame; or

[0108] The drug-containing layer consists of 46.9 wt% levodopa, 31 wt% hydroxypropyl cellulose, 20.1 wt% mannitol, 1 wt% magnesium stearate, 0.1 wt% mint flavor and 0.9 wt% aspartame; or

[0109] The drug-containing layer consists of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 17 wt% mannitol, 5 wt% povidone K30, 1 wt% magnesium stearate and 1 wt% aspartame; or

[0110] The drug-containing layer is composed of 45wt% levodopa, 31wt% hydroxypropyl cellulose, 12wt% mannitol, 5wt% povidone K30, 1wt% magnesium stearate, 5wt% mint flavor and 1wt% aspartame; or

[0111] The drug-containing layer consists of 45 wt% of levodopa, 31 wt% of hydroxypropyl cellulose, 22 wt% of mannitol, 1.0 wt% of magnesium stearate, 0.1 wt% of mint essence and 0.9 wt% of aspartame.

[0112] More preferably, based on the total weight of the coating film, the coating film consists of 50 wt% of cellulose acetate and 50 wt% of copovidone VA64; the coating film consists of 70 wt% of cellulose acetate and 30 wt% of copovidone VA64; the coating film consists of 60 wt% of cellulose acetate and 40 wt% of copovidone VA64.

[0113] Even more preferably, the weight of the coating film is 2.0%, 4.2%, 4.5%, 4.6%, 4.8%, 5.0%, 5.9%, 6.5%, 6.7%, 7.0%, 7.7%, 7.9%, 8.0%, 9.5%, 9.7% or 10% of the weight of the tablet core.

[0114] Preferably, based on the total weight of the osmotic push layer,

[0115] The osmotic push layer is composed of 55wt% sodium carboxymethylcellulose 7H4XF, 5wt% povidone K30, 39wt% sorbitol, 0.5wt% red iron oxide and 0.5wt% magnesium stearate; or

[0116] The osmotic push layer is composed of 55wt% sodium carboxymethylcellulose 7H4XF, 10wt% povidone K30, 34wt% sorbitol, 0.5wt% red iron oxide and 0.5wt% magnesium stearate; or

[0117] The osmotic push layer is composed of 85wt% sodium carboxymethyl cellulose, 3wt% povidone K30, 5wt% sorbitol, 5wt% red iron oxide and 2wt% magnesium stearate; or

[0118] The osmotic push layer consists of 25wt% sodium carboxymethyl cellulose, 9.5wt% povidone K30, 65wt% sorbitol and 0.5wt% magnesium stearate; or

[0119] The osmotic push layer is composed of 60wt% sodium carboxymethylcellulose 7H4XF, 10wt% povidone K30, 26wt% sorbitol, 2wt% red iron oxide and 2wt% magnesium stearate; or

[0120] The osmotic push layer is composed of 40wt% sodium carboxymethylcellulose 7H4XF, 20wt% povidone K30, 36wt% sorbitol, 3.5wt% red iron oxide and 0.5wt% magnesium stearate; or

[0121] The osmotic push layer is composed of 55wt% sodium carboxymethylcellulose 9H4XF, 5wt% povidone K30, 39wt% sorbitol, 0.5wt% red iron oxide and 0.5wt% magnesium stearate; or

[0122] The osmotic push layer consists of 55 wt% sodium carboxymethyl cellulose 7H4XF, 10 wt% hydroxypropyl cellulose, 34 wt% sorbitol, 0.5 wt% red iron oxide and 0.5% magnesium stearate.

[0123] Preferably, based on the total weight of the outer coating,

[0124] The outer coating consists of 23.78 wt% levodopa, 64.22 wt% carbidopa, 10 wt% hydroxypropyl cellulose, 1 wt% aspartame and 1 wt% mint flavor; or

[0125] The outer coating consists of 93wt% of carbomer, 2wt% of hydroxypropyl cellulose and 5wt% of aspartame; or

[0126] The outer coating consists of 75wt% levodopa, 20wt% hydroxypropyl cellulose and 5wt% mint essence; or

[0127] The outer coating consists of 62.15 wt% levodopa, 26.85 wt% carbidopa, 10 wt% hydroxypropyl cellulose, 0.9 wt% aspartame and 0.1 wt% mint flavor; or

[0128] The outer coating consists of 24 wt% levodopa, 65 wt% carbidopa, 10 wt% hydroxypropyl cellulose and 1 wt% aspartame; or

[0129] When the outer coating consists of 54wt% levodopa, 35wt% carbidopa, 10wt% hydroxypropyl cellulose, 0.9wt% aspartame and 0.1wt% mint flavor; or

[0130] When the outer coating consists of 42.8wt% levodopa, 46.2wt% carbidopa, 10wt% hydroxypropyl cellulose, 0.9wt% aspartame and 0.1wt% mint flavor; or

[0131] When the outer coating consists of 28.2 wt % levodopa, 60.8 wt % carbidopa, 10 wt % hydroxypropyl cellulose, 0.9 wt % aspartame and 0.1 wt % mint flavor.

[0132] Even more preferably, the outer coating has a weight percentage of 12.9%, 13.2%, 15.7% or 21.0% relative to the weight of the tablet core.

[0133] Preferably, the pharmaceutical composition comprises a drug-containing layer and a coating film, wherein the drug-containing layer comprises 40 wt% levodopa, 10.8 wt% carbidopa, 20 wt% microcrystalline cellulose, 18.7 wt% mannitol, 5 wt% citric acid, 5 wt% sodium hydroxypropyl methylcellulose, and 0.5 wt% magnesium stearate, with wt% representing the weight percentage in the drug-containing layer; the coating film comprises 50 wt% cellulose acetate film and 50 wt% copovidone VA64, with wt% representing the weight percentage in the coating film; and the weight of the coating film is 2.0% of the weight of the tablet core. A dosage form containing the pharmaceutical composition has a 0.5 mm exit hole mechanically drilled on one side of the drug layer of the coated tablet, and delivers levodopa and carbidopa at average rates of 14.17 mg / hr and 4.59 mg / hr, with 85% of the drug delivered within 12 hours and 10 hours, respectively. The dosage form can be held in the oral cavity until the osmotic layer reaches the delivery port, or it can remain there for 8-9 hours before being swallowed.

[0134] The pharmaceutical composition comprises a drug-containing layer and a coating film, wherein the drug-containing layer comprises 38 wt% levodopa, 50 wt% microcrystalline cellulose, 10 wt% hydroxypropyl methylcellulose, and 2 wt% magnesium stearate, with wt% representing the weight percentage in the drug-containing layer; and the coating film comprises 50 wt% cellulose acetate film and 50 wt% copovidone VA64, with wt% representing the weight percentage in the coating film. The weight of the coating film is 4.5% of the tablet core weight. A dosage form with a film weight gain of 4.5% delivers levodopa at an average rate of 9.4 mg / hr, with 85% of the levodopa delivered within 9.0 hours.

[0135] Alternatively, the pharmaceutical composition comprises a drug-containing layer and a coating film, wherein the drug-containing layer comprises 19.5 wt% levodopa, 20 wt% carbidopa, 50 wt% mannitol, 10 wt% citric acid, and 0.5 wt% magnesium stearate, with wt% representing the weight percentage in the drug-containing layer; and the coating film comprises 50 wt% cellulose acetate film and 50 wt% copovidone VA64, with wt% representing the weight percentage in the coating film. The weight of the coating film is 4.5% of the tablet core weight. A dosage form with a film weight gain of 4.5% delivers levodopa at an average rate of 22.9 mg / hr, with 85% of the levodopa delivered within 13.0 hours.

[0136] Preferably, in one embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer and a coating film, wherein the drug-containing layer is composed of 40wt% of levodopa, 10.8wt% of carbidopa, 31wt% of hydroxypropyl cellulose, 12.7wt% of mannitol, 5wt% of citric acid and 0.5wt% of magnesium stearate, and wt% is its weight percentage in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF or 9H4XF, 5wt% of povidone K30, 39wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% is its weight percentage in the osmotic push layer; the coating film is composed of 70wt% of cellulose acetate film and 30wt% of copovidone VA64, and wt% is its weight percentage in the coating film; the weight of the coating film is 2.0%, 4.0% or 5.0% of the weight of the tablet core. When the sodium carboxymethylcellulose is 7H4XF, one side of the drug layer contains a 0.5 mm exit orifice, and a coating weight of 5.0% of the core tablet weight contains this drug composition, delivering levodopa and carbidopa at average rates of 17.0 mg / hr and 4.6 mg / hr, respectively, with 85% of the drug delivered within 10.0 hours. This dosage form can be held in the mouth until the permeable layer reaches the delivery port, or held in the mouth for 6-7 hours before being swallowed. A dosage form with delivery orifice sizes varying from 0.5 mm, 0.75 mm, and 1.0 mm and a coating weight of 4.0% of the core tablet weight delivers levodopa and carbidopa at average rates of 21.3 mg / hr and 5.7 mg / hr, respectively, with 85% of the drug delivered within 8.0 hours. This dosage form can be held in the mouth until the permeable layer reaches the delivery port, or held in the mouth for 4-5 hours before being swallowed. When the sodium carboxymethylcellulose is 9H4XF, a dosage form with a film weight gain of 2.0% delivers levodopa and carbidopa at average rates of 24.3 mg / hr and 6.6 mg / hr, respectively, with 85% of the drug delivered within 7.0 hours. The dosage form can be maintained in the mouth until the permeation layer reaches the delivery port, or maintained in the mouth for 3-4 hours before being swallowed.

[0137] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer and a coating film, wherein the drug-containing layer is composed of 40wt% of levodopa, 10.8wt% of carbidopa, 31wt% of hydroxypropyl cellulose, 12.7wt% of mannitol, 5wt% of citric acid and 0.5wt% of povidone K30, and wt% is its weight percentage in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 5wt% of povidone K30, 39wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% is its weight percentage in the osmotic push layer; the coating film is composed of 60wt% of cellulose acetate film and 40wt% of copovidone VA64, and wt% is its weight percentage in the coating film; the weight of the coating film is 5.0% of the weight of the tablet core. The dosage form containing the drug composition delivered 85% of the drug within 6 hours. The dosage form can be held in the mouth until the permeable layer reaches the delivery port, or held there for 2-3 hours before being swallowed.

[0138] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer and a coating film, wherein the drug-containing layer is composed of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 16wt% of mannitol, 5% of povidone K30, 1wt% of magnesium stearate, 1% of mint flavor and 1wt% of aspartame, and wt% is its weight percentage in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of povidone K30, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% is its weight percentage in the osmotic push layer; the coating film is composed of 60wt% of cellulose acetate film and 40wt% of copovidone VA64, and wt% is its weight percentage in the coating film; the weight of the coating film is 4.2%, 6.7% or 9.7% of the weight of the tablet core. Dosage forms containing the pharmaceutical composition at film weight gains of 4.2%, 6.7%, and 9.7% delivered levodopa at average rates of 38.3 mg / hr, 27.3 mg / hr, and 21.3 mg / hr, respectively, corresponding to 85% delivery of levodopa within 5.0 hours, 7.0 hours, and 9.0 hours, respectively.

[0139] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer and a coating film, wherein the drug-containing layer is composed of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 16wt% of mannitol, 5% of povidone K30, 1wt% of magnesium stearate, 1% of mint flavor and 1wt% of aspartame, and wt% is its weight percentage in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of povidone K30, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% is its weight percentage in the osmotic push layer; the coating film is composed of 70wt% of cellulose acetate film and 30wt% of copovidone VA64, and wt% is its weight percentage in the coating film; the weight of the coating film is 4.6% or 7.9% of the weight of the tablet core. Dosage forms containing the pharmaceutical composition with film weight gains of 4.6% and 7.9% delivered levodopa at average rates of 25.5 mg / hr and 16.9 mg / hr, respectively, and 85% of the levodopa was delivered in 7.5 hours and 11.5 hours, respectively.

[0140] In another embodiment, the pharmaceutical composition comprises a drug-containing layer, an osmotic push layer, and a coating film, wherein the drug-containing layer comprises 70 wt% levodopa, 9 wt% mannitol, 20 wt% povidone K30, and 1 wt% magnesium stearate, with wt% representing the weight percentage in the drug-containing layer; the osmotic push layer comprises 85 wt% sodium carboxymethylcellulose, 3 wt% povidone K30, 5 wt% sorbitol, 5 wt% red iron oxide, and 2 wt% magnesium stearate, with wt% representing the weight percentage in the osmotic push layer; the coating film comprises 70 wt% cellulose acetate film and 30 wt% copovidone VA64, with wt% representing the weight percentage in the coating film; the weight of the coating film is 4.5% of the weight of the tablet core. The dosage form containing the pharmaceutical composition delivers levodopa at an average rate of 35.0 mg / hr, and delivers 85% of the levodopa within 8.5 hours.

[0141] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer and a coating film, wherein the drug-containing layer is composed of 20wt% of levodopa, 20wt% of carbidopa, 50wt% of hydroxypropyl cellulose, 4wt% of mannitol, 5wt% of aspartame and 1wt% of magnesium stearate, and wt% is its weight percentage in the drug-containing layer; the osmotic push layer is composed of 25wt% of sodium carboxymethyl cellulose, 9.5wt% of povidone K30, 65wt% of sorbitol and 0.5wt% of magnesium stearate, and wt% is its weight percentage in the osmotic push layer; the coating film is composed of 90wt% of cellulose acetate film and 10wt% of copovidone VA64, and wt% is its weight percentage in the coating film; the weight of the coating film is 4.5% of the weight of the tablet core. The dosage form containing the pharmaceutical composition delivered levodopa and carbidopa at an average rate of 7.1 mg / hr, respectively, with 85% of the levodopa / carbidopa delivered within 12 hours.

[0142] Preferably, in one embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating, wherein the drug-containing layer consists of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 16wt% of mannitol, 5% of povidone K30, 1wt% of magnesium stearate, 1wt% of mint flavor and 1wt% of aspartame, where wt% is the weight percentage in the drug-containing layer; the osmotic push layer consists of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of povidone K30, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and the outer coating comprises 1wt% of mannitol, 1wt% of povidone K30, 1wt% of mannitol, 5wt% of povidone K30, 1wt% of magnesium stearate and 1wt% of aspartame, wherein the weight percentage is the weight percentage in the drug-containing layer; the outer coating comprises 1wt% of mannitol, 1wt% of hydroxypropyl cellulose, 16 ... The t% represents the weight percentage in the osmotic push layer; the coating film is composed of 70 wt% cellulose acetate film and 30 wt% copovidone VA64, the wt% represents the weight percentage in the coating film, and the weight of the coating film is 4.8% or 7.7% of the tablet core weight; the outer coating contains an immediate-release composition of 23.78 wt% levodopa, 64.22 wt% carbidopa, 10 wt% hydroxypropylcellulose, 1 wt% aspartame, and 1 wt% mint flavor, the wt% represents the weight percentage in the outer coating, and the weight gain of the outer coating relative to the tablet core is 13.2% and 12.9%, respectively. The release profiles of dosage forms containing this pharmaceutical composition show rapid release of levodopa / carbidopa, followed by sustained release for approximately 8.5 hours and 12.0 hours for dosage forms with a coating film weight gain of 4.8% and 7.7%, respectively. A dosage form with a 4.8% film weight gain can be retained in the mouth for 4-5 hours and then maintained in the mouth during mealtime or throughout the release period. A dosage form with a 7.7% film weight gain can be retained in the mouth for 8-9 hours before swallowing or throughout the release period.

[0143] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating, wherein the drug-containing layer is composed of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 17wt% of mannitol, 5wt% of povidone K30, 1wt% of magnesium stearate and 1wt% of aspartame, and wt% is the weight percentage in the drug-containing layer; the osmotic push layer is composed of 60wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of povidone K30, 26wt% of sorbitol, 2wt% of red iron oxide and The tablet core comprises a 2 wt% magnesium stearate coating, which represents the weight percentage of the tablet core in the osmotic push layer. The coating comprises 70 wt% cellulose acetate and 30 wt% copovidone VA64, which represents the weight percentage of the coating, and the weight of the coating represents 4.8% of the tablet core weight. The outer coating comprises an immediate-release composition of 93 wt% CD, 2 wt% hydroxypropylcellulose, and 5 wt% aspartame, which represents the weight percentage of the outer coating, and the weight gain of the outer coating relative to the tablet core is 13.2%. The immediate-release outer coating of the dosage form initially releases rapidly, followed by a sustained-release release lasting approximately 8 hours. The dosage form can be retained in the mouth for 4-5 hours and then swallowed before eating or retained in the mouth throughout the release period.

[0144] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating, wherein the drug-containing layer is composed of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 12wt% of mannitol, 5wt% of povidone K30, 5wt% of mint flavor, 1wt% of aspartame and 1wt% of magnesium stearate, where wt% is the weight percentage in the drug-containing layer; the osmotic push layer is composed of 40wt% of sodium carboxymethyl cellulose 7H4XF, 20wt% of povidone K30, 36wt% of sorbitol, 3.5wt% of oxidized The tablet comprises iron oxide red and 0.5 wt% magnesium stearate, with wt% representing the weight percentage in the osmotic push layer; the coating comprises 70 wt% cellulose acetate membrane and 30 wt% copovidone VA64, with wt% representing the weight percentage in the coating, and the weight of the coating is 4.8% of the tablet core weight; the outer coating comprises a rapid-release composition of 75 wt% levodopa, 20 wt% hydroxypropyl cellulose, and 5 wt% mint flavor, with wt% representing the weight percentage in the outer coating, and the outer coating increases the weight of the tablet core by 13.2%. The rapid-release outer coating of the dosage form initially releases rapidly, followed by a sustained-release release lasting approximately 8 hours. The dosage form can be retained in the mouth for 4-5 hours and then swallowed before eating or retained in the mouth throughout the release period.

[0145] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating, wherein the drug-containing layer is composed of 62.5wt% of levodopa, 31wt% of hydroxypropyl cellulose, 4.5wt% of mannitol, 0.1wt% of mint flavor, 0.9wt% of aspartame and 1wt% of magnesium stearate, where wt% is the weight percentage of each component in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of hydroxypropyl cellulose, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% The weight percentage of each component in the osmotic push layer is as follows: the coating film is composed of 70 wt% of cellulose acetate film and 30 wt% of copovidone VA64, the weight percentage is the weight percentage of each component in the coating film, and the mass of the coating film is 6.5% of the mass of the tablet core; the outer coating contains a rapid-release composition of 62.15 wt% of levodopa, 26.85 wt% of carbidopa, 10 wt% of hydroxypropyl cellulose, 0.9 wt% of aspartame and 0.1 wt% of mint flavor, the weight percentage is the weight percentage of each component in the outer coating, and the outer coating is 21.0% by weight relative to the weight of the tablet core.

[0146] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating, wherein the drug-containing layer is composed of 46.9wt% of levodopa, 31wt% of hydroxypropyl cellulose, 20.1wt% of mannitol, 0.1wt% of mint flavor, 0.9wt% of aspartame and 1wt% of magnesium stearate, where wt% is the weight percentage of each component in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of hydroxypropyl cellulose, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% The weight percentage of each component in the osmotic push layer is as follows: the coating film is composed of 70 wt% of cellulose acetate film and 30 wt% of copovidone VA64, the weight percentage of each component in the coating film is as follows, and the mass of the coating film is 6.5% of the mass of the tablet core; the outer coating contains a rapid-release composition of 62.15 wt% of levodopa, 26.85 wt% of carbidopa, 10 wt% of hydroxypropyl cellulose, 0.9 wt% of aspartame and 0.1 wt% of mint flavor, the weight percentage of each component in the outer coating is as follows, and the weight gain of the outer coating relative to the tablet core is 15.7%.

[0147] In a specific preferred embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating; wherein the drug-containing layer is composed of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 16wt% of mannitol, 5wt% of povidone K30, 1wt% of magnesium stearate, 1wt% of mint flavor and 1wt% of aspartame, and wt% is the weight percentage of each component in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of hydroxypropyl cellulose, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% is the weight percentage of each component in the drug-containing layer. The weight percentage of the osmotic push layer; the coating film is composed of 70wt% cellulose acetate and 30wt% copovidone V64, where wt% represents the weight percentage of each component in the coating film; the cellulose acetate is cellulose acetate containing 39.8wt% acetyl groups, and the weight of the coating film is 5.9% of the weight of the tablet core; and the outer coating is composed of 64.22wt% levodopa, 23.78wt% carbidopa, 10wt% hydroxypropylcellulose, 1wt% aspartame, and 1% mint flavor, where wt% represents the weight percentage of each component in the outer coating; the weight of the outer coating is 13.1% of the total weight of the tablet core and coating film. When the coating solution solvent of the outer coating is anhydrous ethanol, the content of the carbidopa-related genotoxic impurity hydrazine in the resulting dosage form is 1.7ppm, and the content of the carbidopa-related impurity dihydroxyphenylacetone (DHPA) is 0.21%. When the coating solvent of the outer coating is purified water, the outer coating solid suspension concentration is 10.0wt%, including 24.0wt% levodopa, 65.0wt% carbidopa monohydrate, 10.0wt% hydroxypropylcellulose, and 1.0wt% aspartame, calculated as percentage by weight; the resulting dosage form has a carbidopa-related genotoxic impurity hydrazine content of 3.8ppm, and a carbidopa-related impurity DHPA impurity content of 0.28%. When the coating solvent of the outer coating is anhydrous ethanol, the resulting dosage form has significantly lower levels of carbidopa-related genotoxic impurities hydrazine and DHPA than the dosage form obtained when the coating solvent of the outer coating is purified water. The immediate-release outer coating of the dosage form initially releases rapidly, followed by a sustained, constant-rate release for approximately 8 hours. The osmotic delivery system can be maintained in the oral cavity for 3-5 hours and then swallowed before eating or maintained in the oral cavity throughout the release period.

[0148] In a specific preferred embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating; the drug-containing layer is composed of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 22wt% of mannitol, 0.9wt% of aspartame, 0.5wt% of magnesium stearate and 0.1wt% of mint flavor, and wt% is the weight percentage of each component in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of hydroxypropyl cellulose, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% is the weight percentage of each component in the osmotic push layer. The weight percentage of each component in the layer; the coating film is composed of 70wt% cellulose acetate and 30wt% copovidone V64, where wt% is the weight percentage of each component in the coating film; wherein the cellulose acetate is a cellulose acetate film containing 39.8wt% acetyl groups, and the weight of the coating film is 6.5% of the weight of the tablet core; and, the outer coating is composed of 54wt% levodopa, 35wt% carbidopa, 10wt% hydroxypropylcellulose, 0.9wt% aspartame, and 0.1wt% mint flavor, where wt% is the weight percentage of each component in the outer coating; the weight of the outer coating is 13.1% of the total weight of the tablet core and coating film. The final dosage form contains an immediate-release coating layer of 62.5mg levodopa and 37.5mg carbidopa, and 187.5mg levodopa is contained in the controlled-release drug layer. The immediate release coating of the dosage form releases rapidly first, followed by a sustained release for approximately 8 hours. The osmotic delivery system can be retained in the mouth for 4-5 hours and then swallowed before eating or retained in the mouth throughout the release period.

[0149] In a specific preferred embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating; the drug-containing layer is composed of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 22wt% of mannitol, 0.9wt% of aspartame, 0.5wt% of magnesium stearate and 0.1wt% of mint flavor, and wt% is the weight percentage of each component in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of hydroxypropyl cellulose, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% is the weight percentage of each component in the osmotic push layer. The weight percentage of the tablet core is 70wt%; the coating film is composed of 70wt% cellulose acetate and 30wt% copovidone V64, where wt% is the weight percentage of each component in the coating film; wherein the cellulose acetate is a cellulose acetate film containing 39.8wt% acetyl groups, and the weight of the coating film is 7.0% of the tablet core weight; and, the outer coating is composed of 42.8wt% levodopa, 46.2wt% carbidopa, 10wt% hydroxypropylcellulose, 0.9wt% aspartame, and 0.1wt% mint flavor, where wt% is the weight percentage of each component in the outer coating; the weight of the outer coating is 13.1% of the total weight of the tablet core and coating film. The final dosage form contains an immediate-release coating layer of 37.5mg levodopa and 37.5mg carbidopa, and 112.5mg levodopa is contained in a controlled-release drug layer. The immediate release coating of the dosage form releases rapidly first, followed by a sustained release for approximately 8 hours. The osmotic delivery system can be retained in the mouth for 4-5 hours and then swallowed before eating or retained in the mouth throughout the release period.

[0150] In a specific preferred embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic push layer, a coating film and an outer coating; the drug-containing layer is composed of 45wt% of levodopa, 31wt% of hydroxypropyl cellulose, 22wt% of mannitol, 0.9wt% of aspartame, 1wt% of magnesium stearate and 0.1wt% of mint flavor, and wt% is the weight percentage of each component in the drug-containing layer; the osmotic push layer is composed of 55wt% of sodium carboxymethyl cellulose 7H4XF, 10wt% of hydroxypropyl cellulose, 34wt% of sorbitol, 0.5wt% of red iron oxide and 0.5wt% of magnesium stearate, and wt% is the weight percentage of each component in the osmotic push layer. The tablet core comprises a tablet coating comprising 70 wt% cellulose acetate and 30 wt% copovidone V64, with wt% representing the weight percentage of each component in the coating. The cellulose acetate is a cellulose acetate film containing 39.8 wt% acetyl groups, and the weight of the coating is 9.0% of the tablet core weight. The outer coating comprises 28.2 wt% levodopa, 60.8 wt% carbidopa, 10 wt% hydroxypropylcellulose, 0.9 wt% aspartame, and 0.1 wt% mint flavor, with wt% representing the weight percentage of each component in the outer coating. The weight of the outer coating is 13.1% of the total weight of the tablet core and coating. The final dosage form comprises an immediate-release coating layer comprising 18.75 mg levodopa and 37.5 mg carbidopa, with 56.25 mg levodopa contained in a controlled-release drug layer. The immediate release coating of the dosage form releases rapidly first, followed by a sustained release for approximately 8 hours. The osmotic delivery system can be retained in the mouth for 4-5 hours and then swallowed before eating or retained in the mouth throughout the release period.

[0151] Among them, the preparation method of the above-mentioned outer coating comprises: dissolving the above-mentioned weight percentages of the outer coating components in anhydrous ethanol to prepare a coating solution, preferably, the ratio of the outer coating components to anhydrous ethanol is 1:10. In this pharmaceutical composition, carbidopa is only present in the immediate-release outer coating, and the sustained-release core portion does not contain carbidopa. This dosage form has the following advantages: the content of carbidopa-related genotoxic impurities hydrazine and dihydroxyphenylacetone (DHPA) is lower. When the coating solution solvent of the outer coating is anhydrous ethanol, the carbidopa-related genotoxic impurities hydrazine and DHPA in the resulting dosage form are significantly lower than the dosage form obtained when the coating solution solvent of the outer coating is pure water.

[0152] Unless otherwise specified, the preparation method of the above-mentioned pharmaceutical composition is a conventional preparation method in the art.

[0153] Preferably, as described above, the pharmaceutical composition is an osmotic pump controlled-release drug delivery system. Preferably, the osmotic pump controlled-release drug delivery system is a controlled-release tablet. More preferably, the controlled-release tablet is cylindrical with a diameter of 5-10 mm and a height of 5-30 mm, or a caplet with a length of 10-25 mm and a width of 5-10 mm. Most preferably, each controlled-release tablet contains 62.5 mg of CD and 500 mg of LD, or 62.5 mg of CD and 375 mg of LD, or 62.5 mg of carbidopa and 250 mg of levodopa, or 50 mg of carbidopa and 500 mg of levodopa, or 37.5 mg of carbidopa and 375 mg of levodopa.

[0154] To solve the above technical problems, one of the technical solutions of the present invention is: a method for using the above-mentioned controlled-release dosage form, namely, placing the controlled-release platform in the personalized retention platform, and fixing the retention platform on the matching teeth in the oral cavity; after maintaining it for 4-24 hours, removing the controlled-release dosage form, replacing it with a new controlled-release platform, and re-fixing the retention platform on the matching teeth in the oral cavity to enable it to continuously and stably release the drug.

[0155] In order to solve the problem in the prior art that some patients may have a risk of the applicator falling off after a wide mouth opening or other action, the present invention discloses another technical solution: an oral applicator comprising a core component and a fixing device, wherein the core component comprises an integrally formed molar anastomotic functional area and a drug loading functional area;

[0156] When the oral drug delivery device is fixed in the oral cavity, the drug-carrying functional area is located in the space between the teeth and the cheek, or the drug-carrying functional area is located in the space between the teeth and the tongue;

[0157] The molar anastomotic functional area includes a first section close to the drug-carrying functional area and a second section away from the drug-carrying functional area; one end of the first section and the second section are connected to each other, and the other end is open, forming a U-shaped structure; the first section and the second section are respectively used to anastomose with the buccal side and the lingual side of the tooth, so as to fix the drug-carrying functional area on the tooth;

[0158] The drug-carrying functional area includes a first ring and a second ring arranged coaxially; the axial clamping space formed between the first ring and the second ring is used to fix the drug;

[0159] The fixing device is a fixator or a fixing layer, which is used to strengthen the fixing effect of the core component on the teeth;

[0160] When the fixing device is a fixer:

[0161] When the oral applicator is in use, the lingual side, buccal side and occlusal surface of the retainer are aligned with the lingual side, buccal side and occlusal surface of the teeth and covered on the outer peripheral surface of the teeth; the retainer also covers the molar anastomotic functional area;

[0162] When the fixing device is a fixing layer:

[0163] The fixing layer is attached to outer surfaces of the first section and the second section for contacting teeth.

[0164] In the present disclosure, the oral applicator is similar to the oral retention device described above.

[0165] In the present disclosure, the first ring and the second ring are preferably located on the buccal side of the first or second molar.

[0166] In the present disclosure, the fixture and the molar anastomotic functional area are preferably connected by mechanical assembly, mechanical connection or adhesive bonding.

[0167] Among them, the mechanical assembly is preferably embedded, and a slot is provided on the fixture at the position corresponding to the drug-carrying functional area to achieve detachable fixation of the fixture and the core component. The embedding means that the molar anastomosis functional area is embedded in the space formed on both sides of the fixture.

[0168] The mechanical connection is preferably welding, riveting or bolting.

[0169] The adhesive is preferably one or more of pressure-sensitive adhesive, starch adhesive, latex, epoxy resin and polyurethane acrylate.

[0170] In the present disclosure, the fixing layer is preferably also attached to other outer surfaces of the first section and the second section.

[0171] In the present disclosure, the first ring is close to the open end of the molar anastomosis functional area, and the second ring is far away from the open end of the molar anastomosis functional area. The first ring and the second ring are preferably solid or hollow ring structures.

[0172] Wherein, the hollow ring structure is a closed loop or an open loop.

[0173] The shape of the annular structure is preferably one or more of circular, elliptical and polygonal.

[0174] The shapes of the annular structures of the first ring and the second ring are preferably circular; the hollow area of ​​the first ring is preferably smaller than the hollow area of ​​the second ring, and the tablet can be inserted from the second ring to the first ring.

[0175] In the present disclosure, the material of the core component is preferably one of titanium, stainless steel, cobalt-chromium alloy, cobalt-chromium-molybdenum alloy or precious metal, more preferably cobalt-chromium alloy, and the material of the core component meets the standards of materials used in dentistry.

[0176] In the present disclosure, the material of the fixator is preferably one or more of polyvinyl chloride, polyethylene terephthalate, polyethylene terephthalate-1,4-cyclohexanedimethanol, polyurethane, polyamide, ethylene-vinyl acetate copolymer, polycaprolactone, high-density polyethylene, polypropylene, epoxy acrylate, methacrylate, and polyurethane acrylate; more preferably, polyethylene terephthalate or ethylene-vinyl acetate copolymer. The material of the fixator meets medical grade standards.

[0177] In the present disclosure, the material of the fixing layer is preferably one or more of polyvinyl chloride, polyethylene terephthalate, polyethylene terephthalate-1,4-cyclohexanedimethanol, polyurethane, polyamide, ethylene-vinyl acetate copolymer, polycaprolactone, high-density polyethylene, polypropylene, cellulose acetate, hydroxypropyl cellulose and copovidone, more preferably polyethylene terephthalate or copovidone, and the materials of the fixing layer meet medical grade standards.

[0178] In the present disclosure, the thickness of the fixing layer is preferably 0.01 mm to 1 mm.

[0179] In the present disclosure, the number of teeth covered by the retainer can be adjusted according to the tooth condition and wearing security. The length of the retainer is preferably corresponding to the length of 4-16 teeth in the upper or lower jaw, and more preferably corresponding to the length of 5-9 teeth in the upper or lower jaw.

[0180] In the present disclosure, the length of the molar anastomotic functional area is preferably corresponding to the length of 2-5 teeth in the mandibular.

[0181] Among them, those skilled in the art should understand that the length is a length that enables the fixture or the molar anastomotic functional area to cover the number of teeth, and does not exceed the number of teeth in the target range.

[0182] In a preferred embodiment, the fixture is connected to the molar anastomosis functional area in an embedded manner, and a slot is provided on the fixture at a position corresponding to the drug-loaded functional area to achieve detachable fixation of the fixture and the core component; the length of the molar anastomosis functional area corresponds to the length of the mandibular first and second premolars and the first and second molars; the first ring and the second ring are circular closed rings.

[0183] In a preferred embodiment, the fixture is connected to the molar anastomosis functional area in an embedded manner; the length of the molar anastomosis functional area corresponds to the length of the mandibular first and second premolars and the first and second molars; the first ring and the second ring are elliptical closed rings.

[0184] In a preferred embodiment, the fixture is connected to the molar anastomosis functional area in an embedded manner; the length of the molar anastomosis functional area corresponds to the length of the maxillary second premolar and the first, second and third molars, and the first ring and the second ring are circular closed rings.

[0185] In a preferred embodiment, the fixture is connected to the molar anastomosis functional area by bonding with a pressure-sensitive adhesive; the length of the molar anastomosis functional area corresponds to the length of the first, second and third molars; the first ring and the second ring are polygonal closed rings.

[0186] In a preferred embodiment, the fixing layer is attached to the entire outer surface of the first section of the U-shaped structure and the second section of the U-shaped structure; the length of the molar anastomosis functional area corresponds to the length of the mandibular first and second premolars and the first and second molars; the first ring and the second ring are circular closed rings.

[0187] In a preferred embodiment, a pair of clamping walls are symmetrically provided on the first ring along the direction of the open end of the molar anastomotic functional area.

[0188] Another technical solution disclosed herein is: a method for preparing the above-mentioned oral applicator, which includes the following steps: when the fixing device is a fixer, combining the fixer with the integrally formed first section and second section in a coated form; when the fixing device is a fixing layer, affixing the fixing layer to the outer surface of the integrally formed first section and second section.

[0189] In the present disclosure, the preparation method of the core component preferably includes laser casting, injection molding or die molding.

[0190] Among them, the laser melting and casting steps are preferably: scanning the subject's oral cavity or taking an oral mold to make a plaster model and then scanning to obtain the subject's oral data; using three-dimensional design software and dental design software to respectively design the drug-loading functional area and molar anastomosis functional area of ​​the core component, and combining them in the dental design software to generate a core component design file; preparing the core component by laser melting and casting, grinding, polishing, and cleaning.

[0191] The injection molding steps are preferably as follows: taking a mouth mold of a subject to make a plaster model; using dental wax as a material to prepare a dental wax model on the plaster model, and preparing the core components by a traditional injection molding process.

[0192] In the present disclosure, the method for preparing the fixator preferably includes lamination, molding, cutting or 3D printing.

[0193] The laminating step is preferably as follows: the raw material of the fixture is heated and softened by a laminating machine and then vacuumed, so that the raw material of the fixture covers the dental model and the molar anastomotic functional area.

[0194] The impression making step is preferably as follows: heating and softening the raw material of the fixture, and covering the teeth of the test subject and the molar anatomical functional area.

[0195] In the present disclosure, the raw material of the fastener is preferably as described above.

[0196] In the present disclosure, the method for preparing the fixing layer preferably includes dipping, spraying or lamination.

[0197] The dipping step is preferably as follows: after dissolving the raw material of the fixing layer, immersing the molar anastomotic functional area into the raw material solution of the fixing layer, taking it out, and drying it to form a film.

[0198] The spraying step is preferably as follows: dissolving the raw material of the fixing layer and then applying it to the molar anastomotic functional area by spraying, and drying to form a film.

[0199] The lamination step is preferably as follows: heating and softening the raw material of the fixing layer, covering the molar anastomotic functional area, and then cooling.

[0200] In the present disclosure, the raw material of the fixing layer is preferably as described above.

[0201] In the present disclosure, the fixing device and the covering structure of the first section and the second section are preferably formed by mechanical assembly, mechanical connection or adhesive bonding.

[0202] The mechanical assembly is preferably in the form of embedding.

[0203] When the combination is mechanically assembled, the retainer fits with the dental mold and the core component during the molding process, naturally forming a slot-like structure. At the same time, a buckle design can be added to the molar anastomosis functional area as needed.

[0204] The mechanical connection is preferably in the form of welding, riveting or bolting.

[0205] The adhesive is preferably applied to the outer surfaces of the first and second sections that are in contact with teeth, and more preferably to the entire outer surfaces of the first and second sections.

[0206] Wherein, the coating thickness of the adhesive is preferably no more than 1.0 mm.

[0207] Another technical solution disclosed herein is: an application of the above-mentioned oral medication device, characterized in that: when the fixing device is a retainer: the lingual side, buccal side and occlusal surface of the retainer are aligned with the lingual side, buccal side and occlusal surface of the teeth and covered on the outer peripheral surface of the teeth; the drug-carrying functional area is placed in the space between the teeth and the cheek, or the drug-carrying functional area is placed in the space between the teeth and the tongue; and the retainer covers the molar-aligning functional area;

[0208] When the fixing device is a fixing layer: the drug-carrying functional area is placed in the space between the teeth and the cheek, or the drug-carrying functional area is placed in the space between the teeth and the tongue.

[0209] Yet another technical solution disclosed herein is: a controlled release platform, as described above.

[0210] As mentioned above, the controlled release platform or pharmaceutical composition of the present invention can also be referred to as an osmotic pump tablet. The osmotic pump tablet disclosed herein can be used in conjunction with the aforementioned oral retention device or oral delivery device.

[0211] Yet another aspect of the present disclosure relates to an osmotic pump tablet, comprising a tablet core and a coating film wrapping the tablet core, wherein the coating film has drug release holes, the tablet core comprises a drug-containing layer, and the drug-containing layer comprises an active pharmaceutical ingredient, a hydrophilic polymer, and a surfactant, wherein the hydrophilic polymer comprises hydroxypropyl cellulose and the surfactant comprises poloxamer.

[0212] In some embodiments, based on the total weight of the drug-containing layer, the content of the hydrophilic polymer is 5 wt%-25 wt%, such as 10 wt%-20 wt%, such as 10 wt%-15 wt%.

[0213] In some embodiments, the hydroxypropyl cellulose preferably has a weight average molecular weight of about 80,000, a Brookfield viscosity of about 300-600 mPa·s, and a concentration of about 10%.

[0214] In some embodiments, the hydroxypropyl cellulose is hydroxypropyl cellulose EXF.

[0215] In some embodiments, the hydrophilic polymer may also include conventional hydrophilic polymers in the art, such as one or more of hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, and hydroxyethylcellulose. In other words, the hydrophilic polymer is a mixture of hydroxypropylcellulose and one or more selected from hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, and hydroxyethylcellulose.

[0216] In some embodiments, the content of the surfactant is 1 wt%-15 wt%, such as 2 wt%-10 wt%, and further such as 5 wt%-10 wt%, based on the total weight of the drug-containing layer.

[0217] In some embodiments, the poloxamer is poloxamer 407 (P407).

[0218] In some embodiments, the surfactant may also include conventional surfactants in the art, such as one or more of polysorbate, fatty acid glyceride, sodium dodecylbenzene sulfonate, and sodium lauryl sulfate. That is, the surfactant is a mixture of poloxamer and one or more selected from polysorbate, fatty acid glyceride, sodium dodecylbenzene sulfonate, and sodium lauryl sulfate.

[0219] In some embodiments, based on the total weight of the drug-containing layer, the content of the pharmaceutically active ingredient is 50 wt%-75 wt%, such as 55 wt%-65 wt%, and another example is 58 wt%-63 wt%.

[0220] In some embodiments, the pharmaceutically active ingredient is an orally released pharmaceutically active ingredient.

[0221] In some embodiments, the pharmaceutically active ingredient is a topical oral treatment or a drug with an absorption site in the upper gastrointestinal tract.

[0222] In some embodiments, the pharmaceutically active ingredient is selected from one or more of levodopa or its ester or salt, carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin; preferably, one or both of levodopa or its ester and carbidopa. The ester of levodopa may be a levodopa alkyl ester or a deuterated levodopa alkyl ester, such as levodopa methyl hydrochloride. The salt of levodopa may be levodopa ethyl hydrochloride.

[0223] In some further embodiments, the active pharmaceutical ingredient is selected from antifungal drugs and antitumor drugs. The antifungal drugs are selected from one or more of nystatin, fluconazole, posaconazole, isavuconazole, voriconazole, anidulafungin, caspofungin, and micafungin. The antitumor drugs are selected from one or more of 5-fluorouracil, paclitaxel, and capecitabine.

[0224] In some embodiments, the drug-containing layer further comprises other excipients, wherein the other excipients are selected from one or more of a penetrant, a drug carrier, a binder, a lubricant, an antioxidant, and a flavoring agent.

[0225] In some embodiments, the osmotic agent is selected from one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose, lactose, starch, pregelatinized starch, dextrin, and microcrystalline cellulose, such as sorbitol or mannitol. Preferably, the osmotic agent is present in an amount of 0-50 wt %, but not 0, such as 5-20 wt %, and further such as 10.0 wt %, 14.87 wt %, 15.0 wt %, and 19.87 wt %, based on the total weight of the drug-containing layer.

[0226] In some embodiments, the drug carrier is selected from one or more of povidone (e.g., povidone K30 or povidone K29 / 32), copovidone, carbomer, hypromellose, hydroxyethylcellulose, polyethylene oxide, and sodium alginate. Preferably, the content of the drug carrier is 0-50 wt % but not 0 % based on the total weight of the drug-containing layer; for example, 0.5-50 wt %, for example, 5-50 wt %, for example, 5-10 wt %.

[0227] In some embodiments, the binder is selected from one or more of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, povidone (e.g., povidone K30 or povidone K29 / 32), copovidone, and gelatin. Preferably, the binder is present in an amount of 0-50 wt % but not 0 % based on the total weight of the drug-containing layer; e.g., 0.5-50 wt %, further e.g., 5-50 wt %, e.g., 5-10 wt %.

[0228] In some embodiments, povidone can serve as both a hydrophilic polymer, a drug carrier, and a binder.

[0229] In some embodiments, hydroxypropylcellulose can function as both the hydrophilic polymer and the binder.

[0230] In some embodiments, the lubricant is one or more of stearic acid, magnesium stearate, magnesium fumarate stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, talc, and colloidal silicon dioxide, for example, one or both of magnesium stearate and colloidal silicon dioxide. Preferably, the lubricant is present in an amount of 0-3 wt %, but not 0, such as 0.5-2.5 wt %, or even 1-2 wt %, based on the total weight of the drug-containing layer.

[0231] In some embodiments, the antioxidant can be one or more of butylated hydroxytoluene, butylated hydroxyanisole, tert-butylhydroquinone, propyl gallate, vitamin C, and vitamin E, such as butylated hydroxytoluene. Preferably, the antioxidant is present in an amount of 0-1 wt %, but not 0, such as 0.01-0.1 wt %, based on the total weight of the drug-containing layer.

[0232] In some embodiments, the flavoring agent is one or more of aspartame, apple flavor, orange flavor, banana flavor, mint flavor, saccharin sodium, and stevioside, for example, one or both of aspartame and mint flavor. Preferably, the flavoring agent is present in an amount of 0-10 wt %, or for example, 0-2 wt %, based on the total weight of the drug-containing layer, but not zero; for example, 1.0 wt %. When the flavoring agent is a combination of aspartame and mint flavor, the aspartame content is 0.9 wt %, and the mint flavor content is 0.1 wt %.

[0233] In some embodiments, the drug-containing layer comprises a pharmaceutically active ingredient, a hydrophilic polymer, a surfactant, a binder, a penetrant, a lubricant, and a flavoring agent. Alternatively, the drug-containing layer comprises a pharmaceutically active ingredient, a hydrophilic polymer, a surfactant, a binder, a penetrant, a lubricant, an antioxidant, and a flavoring agent. Alternatively, the drug-containing layer comprises a pharmaceutically active ingredient, a hydrophilic polymer, a surfactant, a penetrant, a lubricant, an antioxidant, and a flavoring agent. Alternatively, the drug-containing layer comprises a pharmaceutically active ingredient, a hydrophilic polymer, a surfactant, a binder, a penetrant, and a lubricant.

[0234] In some embodiments, the drug-containing layer comprises any combination of:

[0235] (1) 50 wt% to 75 wt% of a pharmaceutically active ingredient, 5 to 25 wt% of a hydrophilic polymer, 1 to 15 wt% of a surfactant, 0.5 to 50 wt% of a binder, 5 to 20 wt% of a penetrant, 0.5 to 3 wt% of a lubricant, and 1 to 10 wt% of a flavoring agent;

[0236] (2) 50 wt% to 75 wt% of a pharmaceutically active ingredient, 5 to 25 wt% of a hydrophilic polymer, 1 to 15 wt% of a surfactant, 0.5 to 50 wt% of a binder, 5 to 20 wt% of a penetrant, 0.5 to 3 wt% of a lubricant, 0.01 to 1 wt% of an antioxidant, and 1 to 10 wt% of a flavoring agent;

[0237] (3) 50 wt% to 75 wt% of a pharmaceutically active ingredient, 5 to 25 wt% of a hydrophilic polymer, 1 to 15 wt% of a surfactant, 5 to 20 wt% of a penetrant, 0.5 to 3 wt% of a lubricant, 0.01 to 1 wt% of an antioxidant, and 1 to 10 wt% of a flavoring agent;

[0238] (4) 50 wt% to 75 wt% of a pharmaceutically active ingredient, 5 to 25 wt% of a hydrophilic polymer, 1 to 15 wt% of a surfactant, 0.5 to 50 wt% of a binder, 5 to 20 wt% of a penetrant, and 0.5 to 3 wt% of a lubricant.

[0239] In some embodiments, the drug-containing layer comprises 63.0 wt % of levodopa, 10.0 wt % of hydroxypropylcellulose (EXF) (weight average molecular weight of 80,000), 10.0 wt % of poloxamer (P407), 5.0 wt % of povidone (K29 / 32), 10.0 wt % of sorbitol, 0.9 wt % of aspartame, 0.1 wt % of mint flavor and 1.0 wt % of magnesium stearate.

[0240] In some embodiments, the drug-containing layer comprises 58.0 wt % of levodopa, 15.0 wt % of hydroxypropylcellulose (EXF) (weight average molecular weight of 80,000), 5.0 wt % of poloxamer (P407), 5.0 wt % of povidone (K29 / 32), 15.0 wt % of sorbitol, 0.9 wt % of aspartame, 0.1 wt % of mint flavor and 1.0 wt % of magnesium stearate.

[0241] In some embodiments, the drug-containing layer comprises 58.0 wt % of levodopa, 15.0 wt % of hydroxypropylcellulose (EXF) (weight average molecular weight of 80,000), 5.0 wt % of povidone (K29 / 32), 5.0 wt % of poloxamer (P407), 15.0 wt % of sorbitol, 0.9 wt % of aspartame, 0.1 wt % of mint flavor and 1.0 wt % of magnesium stearate.

[0242] In some embodiments, the drug-containing layer comprises 54.9 wt % of levodopa, 3.16 wt % of carbidopa, 15.0 wt % of hydroxypropylcellulose (EXF) (weight average molecular weight of 80,000), 5.0 wt % of povidone (K29 / 32), 14.87 wt % of sorbitol, 5.0 wt % of poloxamer (P407), 0.9 wt % of aspartame, 0.1 wt % of mint flavor, 0.1 wt % of butylated hydroxytoluene and 1.0 wt % of magnesium stearate.

[0243] In some embodiments, the drug-containing layer comprises 54.9 wt % of levodopa, 3.16 wt % of carbidopa, 15.0 wt % of hydroxypropylcellulose (EXF) (weight average molecular weight of 80,000), 19.87 wt % of mannitol, 0.9 wt % of aspartame, 5.0 wt % of poloxamer (P407), 0.1 wt % of mint flavor, 0.1 wt % of butylated hydroxytoluene and 1.0 wt % of magnesium stearate.

[0244] In some embodiments, the drug-containing layer comprises 63.0 wt % of levodopa, 11.0 wt % of hydroxypropylcellulose (EXF), 5.00 wt % of povidone (K29 / 32), 10.0 wt % of sorbitol, 10.0 wt % of poloxamer (P407) and 1.00 wt % of magnesium stearate.

[0245] In some embodiments, the drug-containing layer comprises 63.0 wt % of levodopa, 11.0 wt % of hydroxypropylcellulose (EXF), 5.00 wt % of povidone (K29 / 32), 8.50 wt % of sorbitol, 10.0 wt % of poloxamer (P407), 0.50 wt % of colloidal silicon dioxide and 2.00 wt % of magnesium stearate.

[0246] In some embodiments, the tablet core further comprises a push layer. The drug-containing layer and the push layer are sequentially laminated together to form a bilayer tablet core. The coating film is wrapped around the exterior of the tablet core. In this disclosure, the push layer and the osmotic push layer described above have the same meaning and are interchangeable.

[0247] In some embodiments, the mass ratio of the drug-containing layer to the push layer is about 0.5:1-4:1, for example, 1.5:1-3.5:1.

[0248] In some embodiments, the push layer comprises one or more of a swelling agent, a penetrant, a binder, a lubricant, and a colorant, preferably a combination of a swelling agent, a penetrant, a binder, and a colorant, or a combination of a swelling agent, a penetrant, a binder, a lubricant, and a colorant.

[0249] In some embodiments, the swelling agent is selected from one or more of sodium carboxymethyl starch, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carbomer, sodium alginate, kappa-carrageenan, sodium carboxymethyl cellulose, or polyethylene oxide; for example, sodium carboxymethyl cellulose (7H4XF). Preferably, the swelling agent is present in an amount of 30-95 wt %, for example, 49.0-68.5 wt %, based on the total weight of the push-boost layer.

[0250] In some embodiments, the osmotic agent is selected from one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose, lactose, starch, pregelatinized starch, dextrin, and microcrystalline cellulose, such as sorbitol or mannitol. Preferably, the osmotic agent is present in an amount of 5-70 wt %, for example, 10.0-30.0 wt %, based on the total mass of the push-boost layer.

[0251] In some embodiments, the binder is selected from one or more of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, povidone, copovidone, and gelatin, such as hydroxypropylcellulose (EXF). Preferably, the binder is present in an amount of 3-25 wt %, for example, 20 wt %, based on the total mass of the push-boost layer.

[0252] In some embodiments, the lubricant is one or more of stearic acid, magnesium stearate, magnesium fumarate stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, talc, and, for example, one or both of magnesium stearate and colloidal silicon dioxide. Preferably, the lubricant content is 0-7 wt %, but not 0, based on the total mass of the push-boost layer, such as 0-3 wt %, or 0.5 wt % to 1 wt %.

[0253] In some embodiments, the colorant is one or more of iron oxide red, iron oxide yellow, iron oxide violet, and iron oxide black, for example, iron oxide red. Preferably, the content of the colorant is 0-2 wt % based on the total mass of the boost layer, but not 0, for example, 0.5 wt %.

[0254] In some embodiments, the push-assist layer comprises a swelling agent, a penetrant, a binder, a lubricant, and a colorant.

[0255] In some embodiments, the push layer comprises 49.0 wt% sodium carboxymethylcellulose (7H4XF), 30.0 wt% sorbitol, 20.0 wt% hydroxypropylcellulose (EXF), 0.5 wt% red iron oxide, and 0.5 wt% magnesium stearate.

[0256] In some embodiments, the push layer comprises 68.5 wt% sodium carboxymethylcellulose (7H4XF), 10.0 wt% sorbitol, 20.0 wt% hydroxypropylcellulose (EXF), 0.5 wt% red iron oxide, 0.5 wt% colloidal silicon dioxide, and 0.5 wt% magnesium stearate.

[0257] In some embodiments, the push layer comprises 55.0 wt% sodium carboxymethylcellulose (7H4XF), 34.0 wt% sorbitol, 10.0 wt% hydroxypropylcellulose (EXF), 0.50 wt% red iron oxide, and 0.50 wt% magnesium stearate.

[0258] In some embodiments, the osmotic pump tablet further comprises an isolation layer. The drug-containing layer, the booster layer, and the isolation layer are sequentially stacked together to form a three-layer tablet core. The coating film is wrapped around the outside of the tablet core. Preferably, the isolation layer comprises one or more of ethyl cellulose, cellulose acetate, acrylic resin, and microcrystalline cellulose, such as ethyl cellulose. Preferably, the mass ratio of the drug-containing layer to the isolation layer is (0.01-0.15):1, for example, 0.05:1-0.1:1.

[0259] In some embodiments, the coating film comprises a film-forming material and a pore-forming agent. Preferably, the film-forming material is selected from one or more of cellulose acetate, ethyl cellulose, and acrylic resin, such as cellulose acetate, and another example is cellulose acetate containing 39.8 wt% acetyl groups. Preferably, the content of the film-forming material is 50-70 wt% based on the total mass of the coating film, such as 50 wt%-55 wt%. Preferably, the pore-forming agent is preferably copovidone, such as copovidone VA64. Preferably, the content of the pore-forming agent is 30-50 wt% based on the total mass of the coating film, such as 45 wt%-50 wt%.

[0260] In some embodiments, the coating film further comprises a plasticizer. The plasticizer can be a conventional plasticizer in the pharmaceutical field, for example, one or more selected from polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, triacetin, and castor oil, and another example is triethyl citrate or polyethylene glycol 400. Preferably, the content of the plasticizer is 0-20wt%, for example, 0-5wt%, but not 0, based on the total weight of the coating film.

[0261] In some embodiments, the coating film comprises a film-forming material and a pore-forming agent, or comprises a film-forming material, a pore-forming agent, and a plasticizer.

[0262] In some embodiments, the tensile strength of the coating film is 1-10 MPa.

[0263] In some embodiments, the coating film has an elongation at break of 1.1-2.0.

[0264] In some embodiments, the coating film has an average thickness of 100±8 μm to 200±10 μm.

[0265] In some embodiments, the drug release hole may have a diameter of 0.3 mm to 1.2 mm.

[0266] In some embodiments, the coating film content is 2 wt%-10 wt%, such as 4.5 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 8.0 wt%, 9.0 wt% or 9.5 wt%, based on the total weight of the osmotic pump tablet.

[0267] In some embodiments, the osmotic pump tablet may further include a drug-containing immediate-release outer coating. The drug-containing immediate-release outer coating includes a pharmaceutically active ingredient and pharmaceutical excipients. The pharmaceutically active ingredient includes one or more of levodopa, levodopa esters, levodopa salts, and carbidopa. The pharmaceutical excipients include one or more of a binder, an antioxidant, a plasticizer, and a flavoring agent.

[0268] The pharmaceutical active ingredient preferably comprises levodopa, carbidopa and a combination thereof. The pharmaceutical excipient preferably comprises one or more of a binder, an antioxidant and a plasticizer, preferably a binder.

[0269] The binder, antioxidant, and flavoring agent are all as described above (e.g., those mentioned for the drug-containing layer in the osmotic pump tablet). The plasticizer is all as described above (e.g., those mentioned for the coating film in the osmotic tablet). Here, the binder is preferably hydroxypropylcellulose (EXF). The antioxidant is preferably butylated hydroxytoluene. The plasticizer is preferably triethyl citrate. The flavoring agent is preferably one or both of aspartame and mint essence.

[0270] In some embodiments, the content of the pharmaceutically active ingredient is preferably 70-90 wt%, such as 77.3-77.5 wt%.

[0271] In some embodiments, the binder is present in an amount of 10-20.0 wt %.

[0272] In some embodiments, the content of the antioxidant is preferably 0.5-2.0 wt%, such as 1.47-1.66 wt%.

[0273] In some embodiments, the content of the plasticizer is preferably 1-2 wt%, such as 1.0 wt%.

[0274] In some embodiments, the active pharmaceutical ingredient in the drug-containing immediate-release outer coating comprises levodopa and / or carbidopa. When both active pharmaceutical ingredients are present, the weight of levodopa is 12.5-200 mg; the weight of carbidopa is 10.5-200 mg. The weight ratio of levodopa to carbidopa is preferably 1:1-4:1.

[0275] In some embodiments, the weights of levodopa and carbidopa in the drug-containing rapid-release outer coating are 12.5 mg and 12.5 mg, 18.75 mg and 10.8 mg, 25 mg and 25 mg, 37.5.5 mg and 37.5 mg, 50 mg and 50 mg, 62.5 mg and 62.5 mg, 75 mg and 75 mg, 87.5 mg and 87.5 mg, 100 mg and 100 mg, 1 25 mg and 125 mg, 150 mg and 150 mg, 200 mg and 200 mg, 25 mg and 12.5 mg, 50 mg and 25 mg, 75 mg and 37.5 mg, 100 mg and 50 mg, 150 mg and 75 mg, 200 mg and 100 mg, 50 mg and 12.5 mg, 100 mg and 25 mg, 150 mg and 37.5 mg, or 200 mg and 50 mg. If carbidopa is used in the form of carbidopa monohydrate, the mass of carbidopa here is replaced by the mass of carbidopa monohydrate (replacement can be made in equal proportion according to the mass of carbidopa).

[0276] Preferably, the drug-containing quick-release outer coating comprises a pharmaceutically active ingredient and an excipient, wherein the excipient is a binder hydroxypropylcellulose (EXF). In some embodiments, the content of the pharmaceutically active ingredient is preferably 80-90 wt %. In some embodiments, the content of the binder is 10-20.0 wt %.

[0277] In some embodiments, the drug-containing immediate-release outer coating comprises 46.7 wt % of carbidopa monohydrate, 43.3 wt % of levodopa, and 10.0 wt % of hydroxypropylcellulose (EXF).

[0278] In some embodiments, the drug-containing immediate-release outer coating comprises 37.7 wt % of carbidopa monohydrate, 52.3 wt % of levodopa, and 10.0 wt % of hydroxypropylcellulose (EXF).

[0279] In some embodiments, the drug-containing immediate-release outer coating comprises 27.2 wt % of carbidopa monohydrate, 62.9 wt % of levodopa, and 10.0 wt % of hydroxypropylcellulose (EXF).

[0280] In some embodiments, the drug-containing immediate-release outer coating comprises 90.0 wt % of carbidopa monohydrate and 10.0 wt % of hydroxypropylcellulose (EXF).

[0281] Another aspect of the present disclosure relates to an osmotic pump tablet, which includes any of the following solutions:

[0282] Option (A): The osmotic pump tablet comprises a tablet core, a coating film wrapping the tablet core, and a drug-containing immediate-release outer coating, wherein the coating film has drug-releasing holes, and the tablet core comprises a drug-containing layer, wherein the drug-containing layer comprises a pharmaceutically active ingredient and a hydrophilic polymer but does not contain a surfactant; the hydrophilic polymer comprises povidone K29 / 32; or

[0283] Option (B): The osmotic pump tablet comprises a tablet core, a coating film wrapping the tablet core, and a drug-containing rapid-release outer coating, wherein the coating film has drug-releasing holes, the tablet core comprises a drug-containing layer, and the drug-containing layer comprises active pharmaceutical ingredients and excipients; the drug-containing rapid-release outer coating comprises active pharmaceutical ingredients and pharmaceutical excipients, and the pharmaceutical excipients are adhesives.

[0284] In solution (A), the pharmaceutically active ingredient and the excipients are those mentioned in the present disclosure.

[0285] In embodiment (A), the pharmaceutically active ingredient preferably comprises levodopa and / or carbidopa. In embodiment (A), when the pharmaceutically active ingredient comprises levodopa, the content of levodopa is 19.5-75 wt% based on the total weight of the drug-containing layer; for example, 19.5-70 wt% (e.g., 19.5 wt%, 20 wt%, 38 wt%, 40 wt%, 45 wt%, 46.9 wt%, or 62.5 wt% or 70 wt%). In another embodiment, when the active ingredient comprises carbidopa, the content of carbidopa is 0-20 wt% but not 0%, for example, 10%-20 wt% (e.g., 10.8 wt% of carbidopa monohydrate) based on the total weight of the drug-containing layer.

[0286] In scheme (A), the content of the active pharmaceutical ingredient is 30-75wt%, for example, 38wt%-65wt% (such as 38wt%, 39.5wt%, 40wt%, 45wt%, 50wt% or 70wt%) based on the total weight of the drug-containing layer.

[0287] In solution (A), based on the total weight of the drug-containing layer, the content of the hydrophilic polymer povidone K29 / 32 is preferably 0.5-50 wt %, such as 0.5-20 wt %, and also such as 5-10 wt %.

[0288] In solution (A), the hydrophilic polymer may also be a mixture of povidone K29 / 32 and one or more selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and hydroxyethyl cellulose.

[0289] In solution (A), the excipient is selected from one or more of a filler, a penetrant, a sour agent, a lubricant and a flavoring agent.

[0290] Preferably, when the excipient contains a filler, the filler is one or more of microcrystalline cellulose, hydroxypropyl cellulose, and mannitol. Based on the total weight of the drug-containing layer, the content of the filler is preferably 0-50 wt% but not 0%, preferably 20-50 wt%, and for example 31 wt%.

[0291] Preferably, when the excipient contains an osmotic agent, the osmotic agent is one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, and glucose. Based on the total weight of the drug-containing layer, the content of the osmotic agent is preferably 0-50 wt% but not 0%; for example, 4-50 wt%; for example, 4 wt%, 4.5 wt%, 9 wt%, 12 wt%, 12.7 wt%, 14.87 wt%, 15 wt%, 16 wt%, 16.5 wt%, 17 wt%, 18 wt%, 18.7 wt%, 19.87 wt%, 20.1 wt%, 22 wt%, or 50 wt%.

[0292] Preferably, when the excipient contains an acidulant, the acidulant is one or more of citric acid, sodium citrate, potassium citrate, malic acid, fumaric acid, lactic acid, phosphoric acid, and tartaric acid. Based on the total weight of the drug-containing layer, the content of the acidulant is preferably 0-10 wt % but not 0%, for example 5 wt %-10 wt %.

[0293] Preferably, when the excipient contains a lubricant, the lubricant is one or more of magnesium stearate, magnesium stearate fumarate, talc, and colloidal silicon dioxide, for example, one or both of magnesium stearate and colloidal silicon dioxide. The lubricant is present in an amount of 0.5-3 wt %, for example, 0.5-2.5 wt %, or even 1-2 wt %, based on the total weight of the drug-containing layer.

[0294] Preferably, when the excipient contains a flavoring agent, the flavoring agent is one or more of aspartame (also known as aspartame), apple flavor, orange flavor, banana flavor, mint flavor, saccharin sodium and stevioside, for example, one or both of aspartame and mint flavor (when both are selected, they can be present in any proportion); preferably, the content of the flavoring agent is 0-10wt% based on the total weight of the drug-containing layer, but not 0; for example, 1-6wt%; and for example, 2-5wt%.

[0295] In solution (A), the excipients are preferably any combination of the following: (1) a filler, a penetrant, a hydrophilic polymer, an acidulant, and a lubricant; (2) a filler, a hydrophilic polymer, and a lubricant; (3) a filler, a penetrant, a hydrophilic polymer, a lubricant, and a flavoring agent; (4) a penetrant, a hydrophilic polymer, and a lubricant; (5) a filler, a hydrophilic polymer, a penetrant, and a lubricant; (6) a filler, a penetrant, an acidulant, and a lubricant; (7) a filler, a penetrant, a flavoring agent, and a lubricant; and (8) a filler, an acidulant, and a lubricant. The excipients are preferably a filler, a hydrophilic polymer, a penetrant, and a lubricant.

[0296] In solution (A), the drug-containing layer comprises 30-75 wt% of a pharmaceutically active ingredient, 0.5-20 wt% of a hydrophilic polymer, 20-50 wt% of a filler, 4-50 wt% of an osmotic agent, and 0.5-3 wt% of a lubricant; for example, it comprises 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone K29 / 32, 18.0 wt% of mannitol, and 1.00 wt% of magnesium stearate; or, it comprises 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone K29 / 32, 16.5 wt% of mannitol, 0.50 wt% of colloidal silicon dioxide, and 2.00 wt% of magnesium stearate.

[0297] In options (A) and (B), the tablet core further comprises a boost layer. The drug-containing layer and the boost layer are sequentially stacked together to form a bilayer tablet core. The coating film is wrapped around the exterior of the tablet core. In this disclosure, the boost layer and the osmotic push layer described above have the same meaning and are interchangeable. The boost layers in the osmotic pump tablets are all those described in this disclosure.

[0298] In scheme (A) and scheme (B), the coating films in the osmotic pump tablets are the same as those mentioned in the present disclosure.

[0299] In solution (A) and solution (B), the osmotic pump sheet further comprises an isolation layer, which are all as mentioned in the present disclosure.

[0300] In solution (A), the osmotic pump tablet may further include a drug-containing rapid-release outer coating. The drug-containing rapid-release layer in the osmotic pump tablet is as mentioned in the present disclosure.

[0301] In solution (B), in the drug-containing rapid-release outer coating, the binder is preferably hydroxypropyl cellulose (EXF).

[0302] In solution (B), in the drug-containing rapid-release outer coating, except for pharmaceutical excipients, the drug-containing rapid-release layer in the osmotic pump tablet is as mentioned in the present disclosure.

[0303] In solution (B), the content of the active pharmaceutical ingredient in the drug-containing rapid-release outer coating is preferably 80-90 wt %; the content of the pharmaceutical excipient is preferably 10-20.0 wt %.

[0304] In solution (B), the active pharmaceutical ingredient in the drug-containing rapid-release outer coating comprises levodopa and / or carbidopa. When two active pharmaceutical ingredients are contained, the mass ratio of levodopa to carbidopa is preferably 1:1-4:1.

[0305] In solution (B), the drug-containing layers in the osmotic pump tablet are as mentioned in the present disclosure.

[0306] In solution (B), the drug-containing layer is preferably any combination of the following:

[0307] (1) 30-75 wt% of a pharmaceutically active ingredient, 20-50 wt% of a filler, 4-50 wt% of an osmotic agent, 0.5-20 wt% of a hydrophilic polymer, 5-10 wt% of an acidulant, and 0.5-3 wt% of a lubricant, such as 40.0 wt% of levodopa (LD), 10.8 wt% of carbidopa monohydrate (CD), 20.0 wt% of microcrystalline cellulose, 18.7 wt% of mannitol, 5.0 wt% of hydroxypropyl methylcellulose (HPMC E5), 5.0 wt% of citric acid, and 0.5 wt% of magnesium stearate;

[0308] (2) 30-75 wt% of a pharmaceutically active ingredient, 20-50 wt% of a filler, 0.5-20 wt% of a hydrophilic polymer, and 0.5-3 wt% of a lubricant; for example, 38.0 wt% of levodopa, 50.0 wt% of microcrystalline cellulose, 10.0 wt% of hydroxypropylmethylcellulose, and 2.0 wt% of magnesium stearate;

[0309] (3) 30-75 wt% of a pharmaceutically active ingredient, 20-50 wt% of a filler, 4-50 wt% of an osmotic agent, 5-10 wt% of an acidulant, and 0.5-3 wt% of a lubricant; for example, 40.0 wt% of levodopa, 10.8 wt% of carbidopa monohydrate, 31.0 wt% of hydroxypropylcellulose having an average molecular weight of 80,000, 12.7 wt% of mannitol, 5.0 wt% of citric acid, and 0.5 wt% of magnesium stearate;

[0310] (4) 30-75 wt% of active pharmaceutical ingredient, 20-50 wt% of filler, 4-50 wt% of osmotic agent, 0.5-20 wt% of hydrophilic polymer, 0.5-3 wt% of lubricant and 1-6 wt% of flavoring agent; for example, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (Klucel EXF), 16.0wt% mannitol, 5.0wt% povidone K30, 1.0wt% aspartame, 1.0wt% mint flavor and 1.0wt% magnesium stearate; or 45.0wt% levodopa, 31.0wt% hydroxypropyl cellulose, 17.0wt% mannitol, 5.0wt% povidone K30, 1.0wt% magnesium stearate and 1.0wt% aspartame; or 45.0wt% levodopa, 31.0wt% hydroxypropyl cellulose, 17.0wt% mannitol, 5.0wt% povidone K30, 1.0wt% magnesium stearate and 1.0wt% aspartame;

[0311] (5) 30-75 wt% of a pharmaceutically active ingredient, 4-50 wt% of an osmotic agent, 5-20 wt% of a hydrophilic polymer, and 0.5-3 wt% of a lubricant; for example, 70.0 wt% of levodopa, 9.0 wt% of mannitol, 20.0 wt% of povidone K30, and 1.0 wt% of magnesium stearate;

[0312] (6) 30-75 wt% of a pharmaceutically active ingredient, 20-50 wt% of a filler, 4-50 wt% of an osmotic agent, 1-6 wt% of a flavoring agent, and 0.5-3 wt% of a lubricant; for example, 20.0 wt% of levodopa, 20.0 wt% of carbidopa, 50.0 wt% of hydroxypropylcellulose, 4.0 wt% of mannitol, 5.0 wt% of aspartame, and 1.0 wt% of magnesium stearate; or, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropylcellulose, 22.0 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint flavor, and 1.0 wt% of magnesium stearate;

[0313] (7) 30-75 wt% of a pharmaceutically active ingredient, 20-50 wt% of a filler, 5-10 wt% of an acidulant, and 0.5-3 wt% of a lubricant; for example, 19.5 wt% of levodopa, 20.0 wt% of carbidopa, 50.0 wt% of mannitol, 10.0 wt% of citric acid, and 0.5 wt% of magnesium stearate;

[0314] (8) 30-75 wt% of a pharmaceutically active ingredient, 0.5-20 wt% of a hydrophilic polymer, 20-50 wt% of a filler, 4-50 wt% of an osmotic agent, and 0.5-3 wt% of a lubricant; for example, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (e.g., hydroxypropyl cellulose EXF), 5.00 wt% of povidone (e.g., povidone K29 / 32), 18.0 wt% of mannitol, and 1.00 wt% of magnesium stearate; or, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (e.g., hydroxypropyl cellulose EXF), 5.00 wt% of povidone (e.g., povidone K29 / 32), 16.5 wt% of mannitol, 0.50 wt% of colloidal silicon dioxide, and 2.00 wt% of magnesium stearate.

[0315] One of the technical solutions of the present invention is: use of the above-mentioned osmotic pump tablet in the preparation of a drug for treating motor symptom fluctuations in patients with late-stage Parkinson's disease.

[0316] One of the technical solutions of the present invention is: a method for preparing the osmotic pump tablet as described above, the method for preparing the osmotic pump tablet comprising the following steps:

[0317] S1. preparing the drug-containing layer granules, which comprises the following steps: mixing the active pharmaceutical ingredient and the excipients, and granulating to obtain the drug-containing layer granules;

[0318] S2. Preparing boost layer particles, which comprises the following steps: granulating at least one of the boost layer auxiliary materials to obtain boost layer particles;

[0319] S3, preparing a double-layer tablet core, compressing the drug-containing layer granules and the booster layer granules obtained in steps S1 and S2 to obtain a double-layer tablet core;

[0320] S4. Prepare osmotic pump tablets, wrap the tablet core with a coating film, and drill drug-releasing holes to obtain the tablets;

[0321] S5. Optionally, after step S4, the method further comprises wrapping the osmotic pump tablet with a drug-containing rapid-release coating;

[0322] Optionally, after step S3 and before step S4, a step of preparing an isolation layer is further included; the step of preparing the isolation layer includes tableting the isolation layer material and the double-layer tablet core;

[0323] Step S5 is required in solution (B).

[0324] The preparation method of the osmotic pump tablet preferably comprises the following steps:

[0325] S1. preparing the drug-layered granules, which comprises the following steps: mixing the active pharmaceutical ingredient, a hydrophilic polymer, and a surfactant, optionally with other excipients, and granulating to obtain drug-layered granules;

[0326] S2. Preparing boost layer particles, comprising the following steps: granulating at least one of an expander, a penetrant, a binder, a lubricant, and a colorant to obtain boost layer particles;

[0327] S3, preparing a double-layer tablet core, compressing the drug-containing layer granules and the booster layer granules obtained in steps S1 and S2 to obtain a double-layer tablet core;

[0328] S4. Prepare osmotic pump tablets, wrap the tablet core with a coating film, and drill drug-releasing holes.

[0329] In some embodiments, in steps S1 and S2, the mixing step preferably includes screening the ingredients before mixing. The screening is preferably performed through a 40-mesh screen. The granulation is independently dry granulation, wet granulation, or fluidized bed granulation. When wet granulation is used, the granulation is preferably dried in a fluidized bed after completion. The granulation step preferably includes granulation. The granulation is preferably granulated through a 1.2 mm sieve.

[0330] In some embodiments, in step S3, the tableting method can be a conventional method in the art, wherein the tableting die used is preferably a 7.0 mm round punch.

[0331] In some embodiments, the drug-releasing holes are obtained by laser drilling or mechanical drilling.

[0332] In some embodiments, when the active pharmaceutical ingredient contains levodopa and carbidopa, step S1 preferably includes the following steps:

[0333] (a) mixing levodopa, a hydrophilic polymer, a binder (or a drug carrier) or an osmotic agent, and a flavoring agent, and granulating the mixture to obtain levodopa-containing granules;

[0334] (b) mixing carbidopa monohydrate, a surfactant, and an osmotic agent, and granulating the mixture to obtain carbidopa-containing granules;

[0335] (c) mixing the granules obtained in steps (a) and (b), and then mixing with a lubricant and a flavoring agent, and optionally with an antioxidant, to obtain drug-layered granules.

[0336] Specifically, the raw material components of the drug-containing immediate-release outer coating are mixed with an alcoholic solvent to obtain a solution, which is then sprayed onto the osmotic pump tablet. The alcoholic solvent is preferably ethanol. The resulting solution has a solids content of approximately 10 wt% (solids content refers to the sum of the weight of all solid components of the coating solution divided by the total weight of the coating solution).

[0337] Another technical solution disclosed herein is: a method for using the above-mentioned osmotic pump tablet, that is, placing the osmotic pump tablet in the oral retention device or oral drug delivery device for use.

[0338] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present disclosure.

[0339] The reagents and raw materials used in the present disclosure are commercially available.

[0340] The positive progress effect of the present invention is:

[0341] The osmotic pump tablet disclosed herein has at least any of the following characteristics:

[0342] (1) It can be maintained in the oral cavity for 2-24 hours, and the time for 85% of the active drug to be released is 4-24 hours, for example, 5-16 hours, and the drug can be continuously released in the oral cavity;

[0343] (2) During the drug release process, the active ingredients of the drug will quickly enter the digestive tract and are not likely to be retained or accumulated in the oral cavity. The retention of the active ingredients in the drug release site is less than 10%. The drug content uniformity of the drug-containing rapid-release coating is very good, and its SD value can be as low as 4%.

[0344] (3) The coating film used for controlled release will not rupture; the residual active ingredient in the osmotic pump tablet is less than 15%;

[0345] (4) The released active pharmaceutical ingredient is continuously swallowed into the gastrointestinal tract, providing continuous drug absorption and stable blood drug concentration;

[0346] (5) The osmotic pump tablet may also include a layer of drug-containing rapid-release outer coating, so that the drug release amount and blood drug concentration in the body can be easily adjusted to quickly reach the therapeutic concentration and maintain it within the therapeutic concentration range for 5-16 hours;

[0347] (6) A high-dose osmotic pump tablet containing 200-2000 mg of active pharmaceutical ingredient in a single osmotic pump tablet; in particular, when the active pharmaceutical ingredient includes levodopa, the levodopa loading can be as high as 200 mg-1500 mg; when the active pharmaceutical ingredient includes carbidopa, the carbidopa loading can be as high as 1 mg-200 mg;

[0348] (7) The drug loading of the active ingredient in the drug-containing layer can be as high as 50-75%;

[0349] (8) The drug release rate in the tablets in aqueous media is 8-150 mg / h (the release rate refers to the amount of drug released in milligrams per hour in the dissolution experiment). BRIEF DESCRIPTION OF THE DRAWINGS

[0350] Figures 1A and 1B are schematic diagrams of the controlled release platform (ERP): Figure 1A. Single-layer essential osmotic pump (EOP); Figure 1B. Double-layer osmotic push-pull system.

[0351] Figure 2 is a schematic diagram of a controlled release dosage form (a combination of a controlled release platform ERP and a retention platform REP): 1. The personalized retention component of the retention platform (REP); 2. The controlled release platform (ERP); 3. The drug fixing component of the retention platform (REP).

[0352] Figures 3A-3C are flow charts for manufacturing the controlled-release dosage form (ERP+REP) of the present invention: Figure 3A. A controlled-release dosage form in which the controlled-release platform is a single-layer basic osmotic pump (EOP); Figure 3B. A controlled-release dosage form in which the controlled-release platform is a double-layer osmotic push-pull system; Figure 3C. A controlled-release dosage form in which the controlled-release platform is a double-layer push-pull system with a rapid-release drug outer coating.

[0353] FIG4 illustrates the preparation of the retention platform (REP) described in Example 1: FIG4A . Drug fixation component; FIG4B . Drug fixation component; FIG4C . Drug fixation component; FIG4D . Drug fixation component; FIG4E . Thermoplastic sheet; FIG4F . Personalized retention platform (REP).

[0354] FIG. 5 is a diagram of the drug fixation assembly described in Example 1: FIG. 5A shows the drug fixation assembly; FIG. 5B shows the controlled release platform fixed in the drug fixation assembly.

[0355] Figure 6 is the retention platform (REP) described in Example 2 and Example 3: Figure 6A. Retention platform (REP); Figure 6B. Controlled release platform fixed to the retention platform (REP); Figure 6C. Retention platform (REP) with a self-locking cover; Figure 6D. Controlled release platform fixed to the retention platform (REP); Figure 6E. Controlled release platform + retention platform (REP) with closed cover; Figure 6F. Retention platform (REP) with a flip-up cover; Figure 6G. Controlled release platform fixed to the retention platform (REP); Figure 6H. Controlled release platform + retention platform (REP) with closed cover; Figure 6I. Retention platform (REP) with a cover that can slide up and down; Figure 6J. Controlled release platform fixed to the retention platform (REP); Figure 6K. Controlled release platform + retention platform (REP) with closed cover.

[0356] FIG. 7 shows the retention platform (REP) described in Examples 4 and 5: FIG. 7A shows the retention platform (REP); FIG. 7B shows the controlled release platform fixed to the retention platform (REP).

[0357] FIG8 shows the release curve of the controlled release platform (ERP) described in Example 6. Error bars represent the standard deviation of n=3.

[0358] FIG9 shows the release curve of the controlled release platform (ERP) described in Example 7. Error bars represent the standard deviation of n=3.

[0359] FIG10 shows the release curve of the controlled release platform (ERP) described in Example 8. Error bars represent the standard deviation of n=3.

[0360] FIG. 11 shows the release curve of the controlled release platform (ERP) described in Example 9. Error bars represent the standard deviation of n=3.

[0361] FIG12 shows the release curve of the controlled release platform (ERP) described in Example 10. Error bars represent the standard deviation of n=3.

[0362] FIG13 shows the release curve of the controlled release platform (ERP) described in Example 11. Error bars represent the standard deviation of n=3.

[0363] FIG14 shows the release curve of the controlled release platform (ERP) described in Example 12. Error bars represent the standard deviation of n=3.

[0364] FIG15 shows the release curve of the controlled release platform (ERP) described in Example 13. Error bars represent the standard deviation of n=3.

[0365] Figure 16 shows the release profile of the controlled release platform (ERP) described in Example 23. Error bars represent the standard deviation for n=3.

[0366] Figure 17 shows the release profile of the controlled release platform (ERP) described in Example 24. Error bars represent the standard deviation for n=3.

[0367] Figure 18 shows the release profile of the controlled release platform (ERP) described in Example 25. Error bars represent the standard deviation for n=3.

[0368] Figure 19 shows the release profile of the controlled release platform (ERP) described in Example 26. Error bars represent the standard deviation for n=3.

[0369] Figure 20 shows the release profile of the controlled release platform (ERP) described in Example 27. Error bars represent the standard deviation for n=3.

[0370] FIG21 is a release curve of the controlled release dosage form (ERP+REP) described in Example 29, with error bars representing standard deviation for n=3.

[0371] FIG22 shows a post-insertion oral retention device for tablets according to an embodiment of the present invention, which is composed of a tooth-engaging component 11 and a medicine-carrying component 41 , wherein the medicine-carrying component 41 is composed of a limiter 21 and a ring body 31 , and the ring body 31 has an opening 311 .

[0372] FIG23 shows a front-insertion oral retention device for tablets according to an embodiment of the present invention, which is composed of a tooth-engaging component 12 and a medicine-carrying component 42 , wherein the medicine-carrying component 42 is composed of a stopper 22 and a ring body 32 , and an opening 321 is formed on the ring body 32 .

[0373] Explanation of the accompanying reference numerals: 11: Tooth-fitting member of the rear-insertion oral retention device 21: Limiting member of the rear-insertion oral retention device 31: Ring body of the rear-insertion oral retention device 311: Opening on the ring body of the rear-insertion oral retention device 41: Drug-carrying member of the rear-insertion oral retention device 12: Tooth-fitting member of the front-insertion oral retention device 22: Limiting member of the front-insertion oral retention device 32: Ring body of the front-insertion oral retention device 321: Opening on the ring body of the front-insertion oral retention device 42: Drug-carrying member of the front-insertion oral retention device

[0374] Figure 24 is a schematic diagram of the structure of the various components of the oral applicator of embodiment 35 of the present invention, which consists of a core component 1 and a fixing device 2, wherein the core component 1 includes a molar anastomosis functional area 11 and a drug-carrying functional area 12, and the drug-carrying functional area 12 consists of a first ring 121 and a second ring 122.

[0375] Figure 25 is a structural schematic diagram of the core components in the oral applicator of embodiment 35 of the present invention.

[0376] FIG26 is a schematic diagram of the structure of the holder when the fixing device in the oral applicator of Example 35 of the present invention is a holder.

[0377] FIG27 is a cross-sectional view along the AA plane of FIG24.

[0378] Figure 28 is a schematic structural diagram of the oral applicator of Example 36.

[0379] Figure 29 is a schematic structural diagram of the oral applicator of Example 37.

[0380] Figure 30 is a schematic structural diagram of the oral applicator of Example 40.

[0381] FIG31 is a cross-sectional view along the BB plane of FIG30.

[0382] Figure 32 is a schematic structural diagram of the oral applicator of Example 43.

[0383] The reference numerals are as follows: 1-core component; 2-fixture device; 201-lingual side of the fixture; 202-buccal side of the fixture; 203-occlusal surface of the fixture; 11-molar anastomotic functional area; 12-drug loading functional area; 121-first ring; 122-second ring; 123-clamping wall.

[0384] FIG33 is a release curve of the osmotic pump tablet according to Example 47 of the present invention.

[0385] FIG34 is a release curve of the osmotic pump tablet according to Example 48 of the present invention.

[0386] FIG35 is a release curve of the osmotic pump tablet according to Example 49 of the present invention.

[0387] FIG36 is a release curve of the dosage form of Example 50 of the present invention.

[0388] FIG37 is a release curve of the osmotic pump tablet according to Example 51 of the present invention.

[0389] FIG38 is a release curve of the osmotic pump tablet according to Example 52 of the present invention.

[0390] FIG39 is a release curve of the osmotic pump tablet according to Example 57 of the present invention.

[0391] FIG40 is a release curve of the osmotic pump tablet according to Example 58 of the present invention.

[0392] FIG41 is a release curve of the osmotic pump tablet according to Example 59 of the present invention.

[0393] FIG42 is a release curve of the osmotic pump tablet according to Example 60 of the present invention.

[0394] FIG43 is a release curve of the osmotic pump tablet according to Example 61 of the present invention.

[0395] FIG44 is a release curve of the osmotic pump tablet according to Example 62 of the present invention.

[0396] FIG45 is a release curve of the osmotic pump tablet according to Example 63 of the present invention.

[0397] FIG46 is a release curve of the osmotic pump tablet according to Example 64 of the present invention.

[0398] FIG47 is a soaking experiment of the osmotic pump tablet of comparative example A.

[0399] FIG48 is a release curve of the osmotic pump tablet of Comparative Example A.

[0400] Figure 49 is the release curve of the osmotic pump tablet of Comparative Example B. DETAILED DESCRIPTION

[0401] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0402] Preferred embodiments are listed below, and the present disclosure is described more clearly and completely in conjunction with the accompanying drawings. It should be noted that unless otherwise stated, the relative arrangement and numerical values ​​of the components and steps described in these embodiments do not limit the scope of the present disclosure. The present disclosure is further illustrated below by way of examples, but the present disclosure is not limited to the scope of the embodiments described. The experimental methods for which specific conditions are not specified in the following examples are carried out according to conventional methods and conditions, or are selected according to the product specifications. The active pharmaceutical ingredients (API) used in the present disclosure include but are not limited to levodopa / carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin and gabapentin.

[0403] In one embodiment, the active pharmaceutical ingredient (API) is levodopa and / or carbidopa, which is incorporated into a single-layer osmotic pump (EOP) known in the prior art (U.S. Patents Nos. 3,845,770 and 3,916,899). As shown in FIG1A , the EOP comprises a core containing the API and a rate-controlling membrane surrounding the core. The EOP comprises at least one pore through the membrane so that the LD / CD can be released into the oral cavity through the pore. The core comprises the LD / CD, an osmotic agent, microcrystalline cellulose (MCC), a binder, a lubricant, a flavoring agent (optional), an acidulant (optional), and an antioxidant (optional). The rate-controlling membrane comprises a semipermeable polymer, in whole or in part, that is permeable to water or moisture present in the oral cavity and substantially impermeable to the drug and other optional ingredients that may be present in the core. A representative semipermeable polymer is cellulose acetate having an acetyl content of 32.0-39.8 wt%.

[0404] In another embodiment, LD / CD is incorporated into a two-layer osmotic delivery system (push-pull) known in the art (U.S. Patents Nos. 4,327,725 and 4,612,008). As shown in FIG1B , the push-pull system comprises a two-layer core (a drug-containing pull layer and an osmotic push layer) and a rate-controlling membrane surrounding the core. The push-pull system comprises at least one hole through the membrane on the drug-containing layer side so that the contents of the pull layer can be released into the oral cavity through the hole. The pull layer comprises LD / CD, a hydrophilic polymer, an osmotic agent, an adhesive, a lubricant, a flavoring agent (optional), an acidulant (optional), and an antioxidant (optional). The push layer comprises a high molecular weight hydrophilic polymer, an osmotic agent, an adhesive, a lubricant, and a colorant (optional). The push-pull osmotic delivery system operates by drawing water or moisture into the two-layer core through the rate-controlling membrane, where it hydrates the two layers, thereby causing the osmotic push layer to swell and push the hydrated, dispensable drug-containing layer formulation through the orifice from the system.

[0405] Figure 2 is a schematic diagram of a controlled release dosage form (a combination of a controlled release platform ERP and a retention platform REP). The retention platform includes a personalized retention component and a drug fixing component. The retention component can be customized to fit the corresponding teeth, and the drug fixing component acts as a reservoir to fix the controlled release platform ERP to keep the ERP in place. The personalized retention component of the retention platform REP can fit the second molar and the anterior and posterior teeth. Due to the length of the retention platform REP, it (the REP holding the ERP) is in a non-inhalable position, thereby eliminating the possibility of blockage. The preferred structure of REP is a snap-on or nut-type basket with various mesh sizes to prevent the ERP from falling out. Other structures of REP can be, but are not limited to, a retainer with two clamping arms.

[0406] Figures 3A-3C are flow charts illustrating the manufacture of a controlled-release dosage form (ERP+REP) of the present disclosure. Figure 3A illustrates the manufacture of a controlled-release dosage form in which the controlled-release platform is a single-layer osmotic pump (EOP); Figure 3B illustrates the manufacture of a controlled-release dosage form in which the controlled-release platform is a double-layer osmotic push-pull system; and Figure 3B illustrates the manufacture of a controlled-release dosage form in which the controlled-release platform is a double-layer push-pull system with an immediate-release drug outer coating.

[0407] The retention component REP can be made from polymeric materials or dental titanium using 3D printing, injection molding, or impression molding. Polymeric materials include, but are not limited to, polycaprolactone (PCL), ethylene-vinyl acetate (EVA), high-density polyethylene (HDPE), polypropylene (PP), polyacrylates, and any other tissue-compatible polymer. PCL is a preferred material due to its low melting point and good biocompatibility. Therefore, the personalized retention component of the REP made of PCL can be easily softened in hot water and then conformed to the molar or premolar.

[0408] One of the ERPs disclosed herein is a single-layer, basic osmotic pump and can be manufactured using standard manufacturing techniques. First, the tablet core granules are prepared using a conventional wet granulation method, which can be performed using a high-shear granulator or a fluidized bed granulator. Second, the granules are compressed in a press to form a single-layer tablet core. Next, the tablet core is coated with a film-coating composition. Finally, a channel is drilled through the film-coating.

[0409] Another ERP disclosed herein is a dual-layer push-pull osmotic pump, which can be manufactured as follows. First, a high-shear granulator or fluidized bed granulator can be used to prepare the drug-containing layer granules and the osmotic push layer granules. Next, the granules of these two layers are compressed in a press to form a dual-layer tablet core. Next, the dual-layer tablet core is coated with a film-coating composition, followed by a drying process. Finally, a permeation channel is drilled into one side of the drug-containing layer.

[0410] The coating film of the osmotic dosage form can be formed using an air suspension technique. The method involves suspending and tumbling a single-layer tablet core or a double-layer tablet core in an air stream and a coating composition until a film is uniformly formed around the core. The air suspension process can be achieved using a fluidized bed granulator with a Wurster insert. Acetone or an acetone-ethanol mixed cosolvent can be used as the coating solvent, in which 2.0-5 wt% of the film-forming composition is dissolved. Other film-forming techniques, such as pan coating, can also be used. In a pan coating system, the film-forming composition is deposited on the tablet core by continuously spraying the composition while tumbling in a rotating pan. Typically, the films formed by these techniques have a thickness of 25 to 250 μm, with a preferred thickness of 100 to 150 μm.

[0411] Optionally, the drilled single-layer EOP or dual-layer push-pull system can be coated with an immediate release LD / CD drug layer.

[0412] The personalized retention platform (REP) disclosed herein can be manufactured as follows. The REP is prepared using 3D printing technology. First, an oral image of the individual is obtained using an oral scanner. Next, the REP, i.e., the retainer of the ERP, is designed using CAD / CAM software. Based on the CAD / CAM design, the REP is then manufactured using 3D printing technology or injection molding from a tissue-compatible polymer, dental titanium, cobalt-chromium alloy, or cobalt-chromium-molybdenum alloy.

[0413] The customized retention platform (REP) disclosed herein can also be manufactured using injection molding technology. First, a dental impression material is used to create a plaster model of the patient's teeth. Dental wax is then used to create the REP shape on the plaster model using conventional processes. The REP is then coated with a mixture of embedding powder and water. After solidification, the embedded wax is heated to melt, creating an injection mold cavity in the shape of the REP. Finally, a fully molten cobalt-chromium alloy is poured into the mold cavity at a predetermined temperature. After cooling and solidification, the mold is polished.

[0414] The personalized retention platform (REP) disclosed herein can also be manufactured using mold molding technology. First, a drug fixation component is manufactured, and then an oval thermoplastic sheet is processed using conventional processes. The thermoplastic sheet is then heated to soften it, and the softened thermoplastic sheet is pressed so that it completely wraps around the teeth, forming a personalized retention component that perfectly matches the teeth. The drug fixation component is then quickly embedded into the uncured retention component, cooled and cured to form a personalized retention platform (REP). The personalized retention platform is allowed to cool and return to its original opaque hard sheet state, and the cooled personalized retention platform is removed from the oral cavity.

[0415] Example 1 Preparation of Retention Platform (Mold Forming)

[0416] 1. Prepare a drug fixation assembly made of stainless steel, dental titanium, cobalt-chromium alloy, or cobalt-chromium-molybdenum alloy suitable for the controlled release platform, as shown in Figures 4A, 4B, 4C, and 4D. The assembly can be in the form of one or more reservoirs open at one or both ends. The cross-section of the reservoir can be polygonal, circular, or open with an opening smaller than the minimum diameter of the tablet.

[0417] 2. 50 g of polycaprolactone was processed into an oval thermoplastic sheet with a size of 2.5 cm x 1.5 cm by conventional technology (as shown in FIG4E );

[0418] 3. Preparation of personalized REP: Heat a thermoplastic sheet in hot water at approximately 70°C to soften it and improve its plasticity. When the thermoplastic sheet becomes translucent (approximately 1 minute), remove it and place it on the tooth. Press the softened thermoplastic sheet so that it completely wraps around the tooth, forming a retention component that fits the tooth perfectly. Then quickly embed the stainless steel drug fixation component into the uncured retention component and cool and solidify it into a personalized retention platform (REP). Spray some water briefly to further accelerate cooling. Wait for the personalized retention platform to cool and return to its original opaque hard sheet state, and remove the cooled personalized retention platform from the mouth (as shown in Figure 4F).

[0419] FIG. 5 shows the aforementioned drug fixing assembly: FIG. 5A shows the drug fixing assembly; FIG. 5B shows the controlled release platform fixed in the drug fixing assembly.

[0420] Example 2 Preparation of Retention Platform (Injection Molding)

[0421] According to the following steps, a retention platform that matches the gap between the mandibular molars was prepared by injection molding, as shown in Figure 6.

[0422] First, a dental impression material is used to take a dental impression and prepare a plaster tooth model that is the same as the patient's.

[0423] Dental wax REP shapes were prepared on plaster tooth models using conventional techniques using dental wax;

[0424] The dental wax REP is then wrapped with a mixture of embedding powder and water, and after standing to solidify, the embedded dental wax is heated to melt, thereby obtaining an injection mold cavity in the shape of REP;

[0425] At a certain temperature, completely molten cobalt-chromium alloy is poured into the above-mentioned mold cavity, cooled and solidified, and then polished.

[0426] Example 3 Preparation of Retention Platform (3D Printing)

[0427] According to the following steps, a retention platform that matches the mandibular molar gap was prepared through oral scanning and 3D printing technology, as shown in Figure 6.

[0428] First, an oral image of the individual is obtained using an oral scanner;

[0429] Use CAD / CAM software or dental software to process the scan data, generate an electronic tooth model, convert it into an editable file, and design a personalized retention platform device that perfectly matches the teeth;

[0430] Using cobalt-chromium-molybdenum 3D printing materials, the designed personalized device is printed using 3D printer laser sintering technology.

[0431] Example 4 Preparation of Retention Platform (Injection Molding)

[0432] According to the following steps, a retention platform that matches the periphery of the non-occlusal surface of the mandibular molar was prepared by injection molding (see Figure 7).

[0433] First, a dental impression material is used to take a dental impression and prepare a plaster tooth model that is the same as the patient's.

[0434] Dental wax REP shapes were prepared on plaster tooth models using conventional techniques using dental wax;

[0435] The dental wax REP is then wrapped with a mixture of embedding powder and water, and after standing to solidify, the embedded dental wax is heated to melt, thereby obtaining an injection mold cavity in the shape of REP;

[0436] At a certain temperature, completely molten cobalt-chromium alloy is poured into the above-mentioned mold cavity, cooled and solidified, and then polished.

[0437] Example 5 Preparation of Retention Platform (3D Printing)

[0438] According to the following steps, a retention platform that matches the periphery of the non-occlusal surface of the mandibular molar was prepared through oral scanning and 3D printing technology (see Figure 7).

[0439] First, an oral image of the individual is obtained using an oral scanner;

[0440] Use CAD / CAM software or dental software to process the scan data, generate an electronic tooth model, convert it into an editable file, and design a personalized retention platform device that perfectly matches the teeth;

[0441] Using cobalt-chromium-molybdenum 3D printing materials, the designed personalized device is printed using 3D printer laser sintering technology.

[0442] Example 6 Preparation of Controlled Release Platform

[0443] A dosage form for dispensing the beneficial drugs levodopa and carbidopa into the oral cavity is manufactured as follows: first, a tablet core is prepared, comprising 40.0 wt% of levodopa (LD), 10.8 wt% of carbidopa monohydrate (CD), 20.0 wt% of microcrystalline cellulose, 18.7 wt% of mannitol, 5.0 wt% of hydroxypropyl methylcellulose (HPMC E5), and 5.0 wt% of citric acid, respectively, in weight percentage, and each of these is passed through a 40-mesh stainless steel sieve, and then mixed with purified water and granulated until a uniform wet mass is formed; the wet mass is passed through a 20-mesh stainless steel sieve and dried at 80° C. for 2 hours; the dried granules are passed through an 18-mesh stainless steel sieve, and then mixed with 0.5 wt% of magnesium stearate.

[0444] Then, 500 mg of the drug core particles were compressed into single-layer tablets using a 9.0 mm round punch using a tablet press.

[0445] Next, the monolayer tablet cores were coated with a film coating. The film-forming composition comprised 50 wt% cellulose acetate and 50 wt% copovidone VA 64, calculated by weight. The film-forming composition was dissolved in acetone to form a 4% solids solution. The film-forming composition was sprayed onto the tablet cores in a Glatt GC 1-pan coater using the process parameters listed in the table below to form a film coating (see Table 1 for coating process parameters). The film weight gain of the coated tablets was 2.0%. Finally, a 0.5 mm exit hole was mechanically drilled on the drug layer side of the coated tablets. Residual solvent was removed by drying the dosage form at 40°C and ambient humidity for 24 hours. Release profiles of the final dosage form were measured in 0.1 N aqueous HCl using a USPI backboard. As shown in Figure 8, the final dosage form ERP delivered LD and CD at average rates of 14.17 mg / hr and 4.59 mg / hr, with 85% of the drug delivered by 12 hours and 10 hours, respectively. The ERP osmotic delivery system can remain in the mouth until the push layer reaches the delivery port; or remain there for 8-9 hours and then be swallowed; or be combined with the retention platform REP and fixed on the teeth that match the mouth and remain there for 12 hours.

[0446] Table 1

[0447] Example 7 Preparation of Controlled Release Platform

[0448] A dosage form designed, shaped, and suitable for dispensing the beneficial drugs levodopa and carbidopa monohydrate into the oral cavity is prepared as follows: first, a drug layer composition is prepared, which comprises 40.0 wt% of LD, 10.8 wt% of CD, 31.0 wt% of hydroxypropylcellulose having a weight average molecular weight of 80,000, 12.7 wt% of mannitol, and 5.0 wt% of citric acid. These excipients are sieved through a 40-mesh stainless steel sieve, mixed with 95% ethanol, and granulated until a uniform wet mass is formed; the wet mass is sieved through a 20-mesh stainless steel sieve and dried at 80° C. for 2 hours; the dried granules are sieved through an 18-mesh stainless steel sieve, and then mixed with 0.5 wt% of magnesium stearate.

[0449] Next, a second composition, i.e., an osmotic layer, was prepared, comprising 55.0 wt% sodium carboxymethylcellulose 7H4XF, 39.0 wt% sorbitol, 5.0 wt% povidone K30, and 0.5 wt% red iron oxide; each of these ingredients was passed through a 40-mesh stainless steel sieve and then mixed with 95% ethanol and granulated until a uniform wet mass was formed; the wet mass was passed through a 20-mesh stainless steel sieve and dried at 80° C. for 2 hours; the dried granules were passed through an 18-mesh stainless steel sieve and then mixed with 0.5 wt% magnesium stearate.

[0450] Next, the drug layer and osmotic layer granules were compressed into a double-layer tablet core. First, 500 mg of the drug layer granules were added to a 9 mm round punch of a tablet press and compacted. Then, 250 mg of the osmotic layer granules were added to the punch and the two layers of granules were compressed into a contact double-layer tablet core using a tablet press.

[0451] Next, the bilayer cores were coated with a film coating. The film-forming composition comprised, by weight, 70 wt% cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% copovidone VA 64. The film-forming composition was dissolved in acetone to form a 4% solids solution. The film-forming composition was sprayed onto the bilayer cores in a Glatt GC 1-pan coater using the process parameters listed in Example 6 to form a film coating with a film weight gain of 5.0%. Finally, a 0.5 mm exit hole was mechanically drilled on the drug layer side of the dosage form. Residual solvent was removed by drying the dosage form at 40°C and ambient humidity for 24 hours. The release profile of the final dosage form was measured in 0.1 N aqueous HCl using the USPI paddle method. The final dosage form delivered LD and CD at average rates of 17.0 mg / hr and 4.6 mg / hr, respectively, with 85% LD / CD delivered within 10.0 hours. Figure 9 depicts the consistent release profile of LD and CD. The osmotic delivery system can remain in the mouth until the osmotic layer reaches the delivery port, and either remain there for 6-7 hours and then be swallowed, or be combined with a retention platform REP and fixed to the teeth in the mouth and remain there for 10 hours.

[0452] Example 8 Preparation of Controlled Release Platform

[0453] In this example, the steps of Example 7 were repeated, and the dosage form included the same drug layer, osmotic layer, and coating film as provided in Example 7. In this example, the film weight gain was 4.0%, and the delivery orifice sizes were varied to 0.5 mm, 0.75 mm, and 1.0 mm. The final dosage form produced delivered LD and CD at average rates of 21.3 mg / hr and 5.7 mg / hr, respectively, with 85% of LD / CD delivered within 8.0 hours. As shown in Figure 10, the delivery orifice size had no significant effect on the release profile. This osmotic delivery system can be maintained in the oral cavity until the osmotic layer reaches the delivery orifice, or maintained there for 4-5 hours and then swallowed, or combined with the retention platform REP and fixed to the teeth of the oral cavity for 8 hours.

[0454] Example 9 Preparation of Controlled Release Platform

[0455] In this example, the steps of Example 7 were repeated, with the dosage form consisting of the same drug layer as provided in Example 7, except that the osmotic layer contained sodium carboxymethylcellulose 9H4XF instead of 7H4XF. In this example, the film-forming composition and delivery pore size were also the same as those in Example 6. The weight gain of the coating film for this dosage form was 2.0%. As shown in Figure 11, this dosage form delivered LD and CD at average rates of 24.3 mg / hr and 6.6 mg / hr, respectively, with 85% of the LD / CD ratio delivered within 7.0 hours. This osmotic delivery system can be maintained in the oral cavity until the osmotic layer reaches the delivery port, or maintained there for 3-4 hours and then swallowed, or combined with a retention platform REP and fixed to the teeth of the oral cavity and maintained there for 7 hours.

[0456] Example 10 Preparation of controlled release platform

[0457] In this example, the steps of Example 7 were repeated, with the dosage form consisting of the same drug layer and osmotic layer as those provided in Example 7, except that the film-forming composition comprised, by weight, 60 wt% cellulose acetate having a 39.8% acetyl content and 40 wt% copovidone VA 64. The film weight gain of this dosage form was 5.0%. As shown in FIG12 , the dosage form delivered 85% of the LD / CD within 6 hours. This osmotic delivery system can be maintained in the oral cavity until the osmotic layer reaches the delivery port, or maintained there for 2-3 hours and then swallowed, or combined with a retention platform REP and fixed to the teeth of the oral cavity where it is fitted and maintained there for 6 hours.

[0458] Example 11 Preparation of controlled release platform

[0459] In this example, the procedure of Example 7 was repeated to provide a dosage form.

[0460] In this embodiment, the drug layer comprises 45.0 wt% of LD, 31.0 wt% of hydroxypropylcellulose (Klucel EXF), 16.0 wt% of mannitol, 5.0 wt% of povidone K30, 1.0 wt% of aspartame, 1.0 wt% of mint flavor, and 1.0 wt% of magnesium stearate. The osmotic layer comprises 55 wt% of sodium carboxymethylcellulose 7H4XF, 34.0 wt% of sorbitol, 10.0 wt% of povidone K30, 0.5 wt% of red iron oxide, and 0.5 wt% of magnesium stearate.

[0461] The drug layer (500 mg) and osmotic layer granules (250 mg) were compressed into a bilayer core tablet using a 16×7 caplet-shaped die.

[0462] The bilayer tablet cores were coated with film coatings with weight gains of 4.2, 6.7, and 9.7 wt%, respectively. The film-forming composition comprised 60 wt% cellulose acetate with a 39.8% acetyl content and 40 wt% copovidone VA64. A 1.0 mm exit hole was mechanically drilled in the drug layer side of the dosage form. Residual solvent was removed by drying the dosage form at 40°C and ambient humidity for 24 hours.

[0463] As shown in FIG13 , the dosage forms delivered LD at average rates of 38.3 mg / hr, 27.3 mg / hr, and 21.3 mg / hr with membrane weight gains of 4.2%, 6.7%, and 9.7%, respectively, with 85% of the LD delivered within 5.0 hours, 7.0 hours, and 9.0 hours, respectively.

[0464] Example 12 Preparation of controlled release platform

[0465] In this example, the steps of Example 11 were repeated to provide a dosage form in addition to a film-forming composition. In this example, the bilayer core tablet contained a film-forming composition comprising, by weight, 70 wt% cellulose acetate having a 39.8% acetyl content and 30 wt% copovidone VA 64. The film-forming composition was dissolved in a mixed solvent comprising 90% acetone, 9.0% ethanol, and 1.0% deionized water to form a 4% solids solution. As shown in Figure 14, dosage forms with film weight gains of 4.6 wt% and 7.9 wt% delivered LD at average rates of 25.5 mg / hr and 16.9 mg / hr, respectively, with 85% of the LD delivered in 7.5 hours and 11.5 hours, respectively.

[0466] Example 13 Preparation of Controlled Release Platform

[0467] In this example, the steps of Example 12 were repeated to provide a dosage form. In this example, a dried dosage form having a film weight gain of 4.8% and 7.7% was overcoated with an immediate-release composition comprising 23.78 wt% LD, 64.22 wt% CD, 10.0 wt% hydroxypropylcellulose, 1.0 wt% aspartame, and 1.0 wt% mint flavor (as shown in FIG3 c). The immediate-release overcoating composition was added to ethanol to form a 6.7% solids suspension. The final dosage form comprised an immediate-release overcoat layer of 62.5 mg CD and 25 mg LD, with 225 mg LD contained in a controlled-release drug layer. As shown in FIG15 , the release profile of the dosage form showed rapid release of LD / CD, followed by controlled-release release for approximately 8.5 hours and 12.0 hours, respectively. An osmotic delivery system with a 4.8% film weight gain can be maintained in the oral cavity for 4-5 hours and then maintained during mealtimes or throughout the release period. The osmotic delivery system with a film weight gain of 7.7% can be maintained in the mouth for 8-9 hours before swallowing, or maintained in the mouth during the entire release period, or combined with the retention platform REP and fixed to the teeth in the mouth and maintained there for 12 hours.

[0468] Example 14 Preparation of Controlled Release Platform

[0469] In this example, the steps of Example 6 were repeated, and the dosage form included a drug layer and film-forming composition similar to that provided in Example 6. The drug layer comprised 38.0 wt% of levodopa, 50.0 wt% of microcrystalline cellulose, 2.0 wt% of magnesium stearate, and 10.0 wt% of hydroxypropyl methylcellulose, expressed in weight percentages. The film coating comprised 50 wt% cellulose acetate film containing 39.8 wt% acetyl groups and 50 wt% of copovidone VA64. In this example, the film weight gain was 4.50%. The resulting dosage form delivered levodopa at an average rate of 9.4 mg / hr, with 85% of the levodopa delivered within 9.0 hours.

[0470] Example 15 Preparation of controlled release platform

[0471] In this example, the steps of Example 6 were repeated, and the dosage form included a drug layer and film-forming composition similar to that provided in Example 6. The drug-containing layer comprised 19.5 wt% levodopa, 20.0 wt% carbidopa, 50.0 wt% mannitol, and 10.0 wt% citric acid, calculated by weight percentage. The coating film comprised 50 wt% cellulose acetate film containing 39.8 wt% acetyl groups and 50 wt% copovidone VA64. In this example, the film weight gain was 4.50%. The resulting dosage form delivered levodopa at an average rate of 22.9 mg / hr, with 85% of the levodopa delivered within 13.0 hours.

[0472] Example 16 Preparation of Controlled Release Platform

[0473] In this example, the steps of Example 7 were repeated, and the dosage form included a drug layer, osmotic layer, and film-forming composition similar to those in Example 7. The drug layer comprised 70.0 wt% levodopa, 9.0 wt% mannitol, 20.0 wt% povidone K30, and 1.0 wt% magnesium stearate, calculated by weight. The osmotic layer comprised 85.0 wt% sodium carboxymethylcellulose (7H4XF), 3.0 wt% povidone K30, 5.0 wt% sorbitol, 5.0 wt% red iron oxide, and 2.0 wt% magnesium stearate, calculated by weight. The coating film comprised 70 wt% cellulose acetate film containing 39.8 wt% acetyl groups and 30 wt% copovidone VA64, calculated by weight. In this example, the film weight gain was 4.5%. The resulting dosage form delivered levodopa at an average rate of 35.0 mg / hr, with 85% of the levodopa delivered within 8.5 hours.

[0474] Example 17 Preparation of Controlled Release Platform

[0475] In this example, the steps of Example 7 were repeated, and the dosage form included a drug layer, an osmotic layer, and a film-forming composition similar to those in Example 7. The drug layer comprised, by weight, 20.0% levodopa, 20.0% carbidopa, 50.0% hydroxypropylcellulose, 4.0% mannitol, 5.0% aspartame, and 1.0% magnesium stearate. The osmotic layer comprised, by weight, 25.0% sodium carboxymethylcellulose (7H4XF), 9.5% povidone K30, 65.0% sorbitol, and 0.5% magnesium stearate. The coating film comprised, by weight, 90% cellulose acetate film containing 39.8% acetyl groups and 10% copovidone VA64. In this example, the film weight gain was 4.5%. The final manufactured dosage form delivered levodopa and CD at an average rate of 7.1 mg / hr, respectively, with 85% of the levodopa / CD delivered within 12 hours.

[0476] Example 18 Preparation of Controlled Release Platform

[0477] In this example, the steps of Example 13 were repeated, and the dosage form included a drug layer, permeation layer, film-forming composition, and outer coating similar to those in Example 13. The drug layer comprised 45.0 wt% levodopa, 31.0 wt% hydroxypropylcellulose, 17.0 wt% mannitol, 5.0 wt% povidone K30, 1.0 wt% magnesium stearate, and 1.0 wt% aspartame, by weight percentage. The permeation layer comprised 60.0 wt% sodium carboxymethylcellulose (7H4XF), 10.0 wt% povidone K30, 26.0 wt% sorbitol, 2.0 wt% red iron oxide, and 2.0 wt% magnesium stearate, by weight percentage. The coating film comprised 70 wt% cellulose acetate film containing 39.8 wt% acetyl groups and 30 wt% copovidone VA64, by weight percentage. The weight of the coating film was 4.5% of the weight of the tablet core. The immediate-release outer coating comprises 93.0 wt% CD, 2.0 wt% hydroxypropylcellulose, and 5.0 wt% aspartame, calculated as percentages by weight; the weight of the outer coating is 13.2% of the weight of the core (core plus the first coating of cellulose acetate and copovidone VA64). The immediate-release outer coating of the dosage form provides an initial rapid release followed by a controlled release duration of approximately 8 hours. The osmotic delivery system can be retained in the mouth for 4-5 hours and then swallowed before eating or retained in the mouth throughout the release period, or, in combination with a retention platform REP, secured to the teeth in the mouth and retained there for 8 hours.

[0478] Example 19 Preparation of Controlled Release Platform

[0479] In this example, the steps of Example 13 were repeated, and the dosage form included a drug layer, permeation layer, film-forming composition, and outer coating similar to those in Example 13. The drug layer comprised 45.0 wt% levodopa, 31.0 wt% hydroxypropylcellulose, 12.0 wt% mannitol, 5.0 wt% povidone K30, 5.0 wt% mint flavor, 1.0 wt% magnesium stearate, and 1.0 wt% aspartame, by weight percentage. The permeation layer comprised 40.0 wt% sodium carboxymethylcellulose (7H4XF), 20.0 wt% povidone K30, 36.0 wt% sorbitol, 3.5 wt% red iron oxide, and 0.5 wt% magnesium stearate, by weight percentage. The coating film comprised 70 wt% cellulose acetate film containing 39.8 wt% acetyl groups and 30 wt% copovidone VA64, by weight percentage. The weight of the coating film was 4.5% of the tablet core weight. The immediate-release outer coating comprises 75.0 wt% LD, 20.0 wt% hydroxypropylcellulose, and 5.0 wt% mint flavor, calculated as percentages by weight; the weight of the outer coating is 13.2% of the weight of the core tablet (core tablet + first coating layer of cellulose acetate and copovidone VA64). The immediate-release outer coating of the dosage form initially releases rapidly, followed by a controlled release duration of approximately 8 hours. The osmotic delivery system can be retained in the mouth for 4-5 hours and then swallowed before eating or retained in the mouth throughout the release period, or, in combination with the retention platform REP, fixed to the teeth that match the mouth and retained there for 8 hours.

[0480] Example 20 Preparation of controlled release platform

[0481] In this example, the steps of Example 8 were repeated, and the dosage form included a drug layer, permeation layer, film-forming composition, and outer coating similar to those in Example 8. The drug layer comprised 45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 17.0 wt% mannitol, 5.0 wt% povidone K30, 1.0 wt% magnesium stearate, and 1.0 wt% aspartame, by weight percentage. The permeation layer comprised 55.0 wt% sodium carboxymethyl cellulose (7H4XF), 10.0 wt% hydroxypropyl cellulose, 34.0 wt% sorbitol, 0.5 wt% red iron oxide, and 0.5 wt% magnesium stearate, by weight percentage. The coating film comprised 70 wt% cellulose acetate film containing 39.8 wt% acetyl groups and 30 wt% copovidone VA64, by weight percentage. The weight of the coating film was 5.9% of the weight of the tablet core. The immediate-release outer coating solid suspension has a concentration of 10.0 wt%, comprising 24.0 wt% levodopa, 65.0 wt% carbidopa monohydrate, 10.0 wt% hydroxypropylcellulose, and 1.0 wt% aspartame, calculated by weight. The weight of the outer coating is 13.2% of the weight of the tablet core (tablet core + first coating layer of cellulose acetate and copovidone VA64). When the outer coating solvent is anhydrous ethanol, the resulting dosage form contains 1.7 ppm of the carbidopa-related genotoxic impurity hydrazine and 0.21% of the carbidopa-related impurity dihydroxyphenylacetone (DHPA). When the coating solvent of the outer coating is purified water, the outer coating solid suspension concentration is 10.0wt%, including 24.0%wt% levodopa, 65.0wt% carbidopa monohydrate, 10.0wt% hydroxypropylcellulose, and 1.0wt% aspartame, calculated as percentage by weight; the resulting dosage form has a carbidopa-related genotoxic impurity hydrazine content of 3.8ppm, and a carbidopa-related impurity DHPA impurity content of 0.28%. When the coating solvent of the outer coating is anhydrous ethanol, the resulting dosage form has significantly lower levels of carbidopa-related genotoxic impurities hydrazine and DHPA than the dosage form obtained when the coating solvent of the outer coating is purified water. The immediate-release outer coating of the dosage form initially releases rapidly, followed by a sustained, constant-rate release for approximately 8 hours. The osmotic delivery system can be maintained in the oral cavity for 3-5 hours and then swallowed before eating or maintained in the oral cavity throughout the release period.

[0482] Example 21 Preparation of Controlled Release Platform (62.5 mg CD + 500 mg LD per tablet)

[0483] A dosage form designed, shaped, and suitable for dispensing the beneficial drugs levodopa and carbidopa monohydrate into the oral cavity is prepared as follows: first, a drug layer composition is prepared, which comprises 67.9 wt% of LD, 25.1 wt% of hydroxypropylcellulose having a weight-average molecular weight of 80,000, 5.0 wt% of povidone K30, and 1.0 wt% of aspartame. These excipients are sieved through a 40-mesh stainless steel sieve, mixed with purified water, and granulated until a uniform wet mass is formed; the wet mass is passed through a 4×4 mm sieve and dried at 60° C. for 1 hour; the dried granules are passed through a 1.5 mm sieve, and then mixed with 1.0 wt% of magnesium stearate.

[0484] Next, a second composition, i.e., an osmotic layer, was prepared, comprising 55.0 wt% sodium carboxymethylcellulose 7H4XF, 39.0 wt% sorbitol, 5.0 wt% povidone K30, and 0.5 wt% red iron oxide; each of these ingredients was passed through a 40-mesh stainless steel sieve and then mixed with 95% ethanol and granulated until a uniform wet mass was formed; the wet mass was passed through a 4×4 mm sieve and dried at 80° C. for 2 hours; the dried granules were passed through a Φ1.2 mm sieve and then mixed with 0.5 wt% magnesium stearate.

[0485] Next, the drug layer and osmotic layer granules were compressed into a bilayer tablet core. First, 700 mg of the drug layer granules were added to a 19 × 7.5 mm special-shaped punch of a tablet press and compacted. Then, 350 mg of the osmotic layer granules were added to the punch, and the granules of the two layers were compressed into a contact bilayer tablet core using a tablet press.

[0486] Next, a film coating was applied to the bilayer cores. The film-forming composition comprised, by weight percentage, 70 wt% cellulose acetate having an acetyl content of 39.8 wt% and 30 wt% copovidone VA 64. The film-forming composition was dissolved in acetone to form a 4% solids solution. The film-forming composition was sprayed onto the bilayer cores in a Glatt GC 1 pan coater using the process parameters listed in Example 6 to form a film coating with a film weight gain of 5.0%. Finally, a 1.0 mm exit hole was mechanically drilled on the drug layer side of the dosage form. Residual solvent was removed by drying the dosage form at 40°C and ambient humidity for 72 hours. The immediate-release outer coating comprises 24.1 wt% LD, 64.9 wt% CD, 10.0 wt% hydroxypropylcellulose, and 1.0 wt% aspartame, calculated by weight; the weight of the outer coating is 9.4% of the weight of the tablet core (tablet core + first coating layer of cellulose acetate and copovidone VA64). The immediate-release outer coating of the dosage form provides an initial rapid release followed by a controlled release duration of approximately 16 hours. The osmotic delivery system can be maintained in the oral cavity for 16 hours, remaining in the oral cavity throughout the release period, or, in combination with the retention platform REP, affixed to the teeth in the oral cavity and maintained there for 16 hours.

[0487] Example 22 Preparation of Controlled Release Platform (62.5 mg CD + 375 mg LD per tablet)

[0488] In this example, the steps of Example 20 were repeated. The dosage form included a drug layer, osmotic layer, film-forming composition, and outer coating similar to those in Example 20. The drug layer comprised 53.5 wt% LD, 39.5 wt% hydroxypropylcellulose with a weight-average molecular weight of 80,000, 5.0 wt% povidone K30, 1.0 wt% aspartame, and 1.0 wt% magnesium stearate, calculated by weight percentage. The osmotic layer comprised 55.0 wt% sodium carboxymethylcellulose 7H4XF, 39.0 wt% sorbitol, 5.0 wt% povidone K30, 0.5 wt% red iron oxide, and 0.5 wt% magnesium stearate, calculated by weight percentage. The coating film comprised 70 wt% cellulose acetate film containing 39.8 wt% acetyl groups and 30 wt% copovidone VA64, calculated by weight percentage. The weight of the coating film accounted for 8.0% of the tablet core weight. The immediate-release outer coating comprises 24.05 wt% LD, 64.95 wt% CD, 10.00 wt% hydroxypropylcellulose, and 1.0 wt% aspartame, calculated by weight; the weight of the outer coating is 9.4% of the weight of the core tablet (core plus the first coating layer of cellulose acetate and copovidone VA64). The immediate-release outer coating of the dosage form provides an initial rapid release followed by a controlled release duration of approximately 16 hours. The osmotic delivery system can be maintained in the oral cavity for 16 hours, remaining in the oral cavity throughout the release period, or, in combination with the retention platform REP, affixed to the teeth in the oral cavity and maintained there for 16 hours.

[0489] Example 23 Preparation of Controlled Release Platform (each tablet contains 50 mg CD + 500 mg LD)

[0490] A dosage form designed, shaped, and suitable for dispensing the beneficial drugs levodopa and carbidopa monohydrate into the oral cavity is prepared as follows: First, a drug layer composition is prepared, comprising 62.5 wt% of LD, 31.0 wt% of hydroxypropylcellulose having a weight-average molecular weight of 80,000, 4.5 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint flavor, and 0.5 wt% of magnesium stearate, which is dry-granulated and passed through a 1.2 mm sieve, and then mixed with 0.5 wt% of magnesium stearate.

[0491] Next, a second composition, i.e., an osmotic layer, was prepared, comprising 55.0 wt% sodium carboxymethylcellulose 7H4XF, 34.0 wt% sorbitol, 10.0 wt% hydroxypropyl cellulose, and 0.5 wt% red iron oxide; these excipients were mixed, granulated by dry method, and passed through a 1.2 mm sieve, and then mixed with 0.5 wt% magnesium stearate.

[0492] Next, the drug layer and osmotic layer granules were compressed into a bilayer tablet core. First, 600 mg of the drug layer granules were added to a 19 × 7.5 mm special-shaped punch of a tablet press and compacted. Then, 300 mg of the osmotic layer granules were added to the punch, and the two layers of granules were compressed into a contact bilayer tablet core using a tablet press.

[0493] Next, the bilayer core was coated with a film. The film-forming composition comprised, by weight percentage, 70 wt% cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% copovidone VA 64. The film-forming composition was dissolved in acetone to form a 4% solids solution. The film-forming composition was sprayed onto the bilayer core in a Glatt GC 1-pot coater using the process parameters listed in Example 6 to form a coating film with a film weight gain of 6.5%. Finally, a 1.0 mm exit hole was mechanically drilled on the drug layer side of the dosage form. The immediate-release outer coating comprised 62.15 wt% LD, 26.85 wt% CD, 10.0 wt% hydroxypropyl cellulose, 0.9 wt% aspartame, and 0.1 wt% mint flavor, by weight percentage; the mass of the outer coating was 21.0% of the mass of the core (core + first layer of coating film, cellulose acetate and copovidone VA 64). As shown in Figure 16, the release profile of the dosage form shows a rapid release of LD / CD followed by a controlled release with a release duration of approximately 16 hours. The osmotic delivery system can be maintained in the oral cavity for 16 hours, maintained in the oral cavity throughout the release period, or combined with a retention platform REP and fixed to the teeth in the oral cavity and maintained there for 16 hours.

[0494] Example 24 Preparation of Controlled Release Platform (37.5 mg CD + 375 mg LD per tablet)

[0495] A dosage form designed, shaped, and suitable for dispensing the beneficial drugs levodopa and carbidopa monohydrate into the oral cavity is prepared as follows: First, a drug layer composition is prepared, comprising 46.9 wt% of LD, 31.0 wt% of hydroxypropylcellulose having a weight-average molecular weight of 80,000, 20.1 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint flavor, and 0.5 wt% of magnesium stearate, which is dry-granulated and passed through a 1.2 mm sieve, and then mixed with 0.5 wt% of magnesium stearate.

[0496] Next, a second composition, i.e., an osmotic layer, was prepared, comprising 55.0 wt% sodium carboxymethylcellulose 7H4XF, 34.0 wt% sorbitol, 10.0 wt% hydroxypropyl cellulose, and 0.5 wt% red iron oxide; these excipients were mixed, granulated by dry method, and passed through a 1.2 mm sieve, and then mixed with 0.5 wt% magnesium stearate.

[0497] Next, the drug layer and osmotic layer granules were compressed into a bilayer tablet core. First, 600 mg of the drug layer granules were added to a 19 × 7.5 mm special-shaped punch of a tablet press and compacted. Then, 300 mg of the osmotic layer granules were added to the punch, and the two layers of granules were compressed into a contact bilayer tablet core using a tablet press.

[0498] Next, the bilayer core was coated with a film. The film-forming composition comprised, by weight percentage, 70 wt% cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% copovidone VA 64. The film-forming composition was dissolved in acetone to form a 4% solids solution. The film-forming composition was sprayed onto the bilayer core in a Glatt GC 1-pan coater using the process parameters listed in Example 6 to form a coating film with a film weight gain of 6.5%. Finally, a 1.0 mm exit hole was mechanically drilled on the drug layer side of the dosage form. The immediate-release outer coating comprised 62.15 wt% LD, 26.85 wt% CD, 10.0 wt% hydroxypropyl cellulose, 0.9 wt% aspartame, and 0.1 wt% mint flavor, by weight percentage; the mass of the outer coating was 15.7% of the mass of the core (core + first layer of coating film, cellulose acetate and copovidone VA 64). As shown in Figure 17, the release profile of the dosage form shows a rapid release of LD / CD followed by a controlled release with a release duration of approximately 16 hours. The osmotic delivery system can be maintained in the oral cavity for 16 hours, maintained in the oral cavity throughout the release period, or combined with the retention platform REP and fixed to the teeth in the oral cavity and maintained there for 16 hours.

[0499] Example 25 Preparation of Controlled Release Platform (37.5 mg CD + 250 mg LD per tablet)

[0500] First, a drug layer composition was prepared, comprising 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose, 22.0 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint flavor, and 0.5 wt% of magnesium stearate. The compositions were sieved through a 40-mesh stainless steel sieve and then granulated using a dry granulator to obtain dry granules, which were then mixed with 0.5 wt% of magnesium stearate.

[0501] Next, a second composition, i.e., an osmotic layer, was prepared, comprising 55.0 wt% sodium carboxymethylcellulose 7H4XF, 34.0 wt% sorbitol, 10.0 wt% hydroxypropyl cellulose, and 0.5 wt% red iron oxide; each of these ingredients was passed through a 40-mesh stainless steel sieve and then granulated using a dry granulator to obtain dry granules, which were then mixed with 0.5 wt% of magnesium stearate.

[0502] Next, the drug layer and osmotic layer granules were compressed into bilayer tablet cores. First, 417 mg of drug layer granules were added to a 16 x 7 mm special-shaped punch of a tablet press and compacted. Then, 208 mg of osmotic layer granules were added to the punch, and the two layers of granules were compressed into contact bilayer tablet cores using a tablet press.

[0503] Next, the bilayer cores were coated with a film coating. The film-forming composition comprised, by weight, 70% cellulose acetate with an acetyl content of 39.8% and 30% copovidone VA 64. This film-forming composition was dissolved in acetone to form a 4% solids solution. The film-forming composition was sprayed onto the bilayer cores in a Glatt GC 1-pan coater using the process parameters outlined in Example 6 to form a film coating with a film weight gain of 6.5%. Finally, a 1.0 mm exit hole was laser-drilled on the drug layer side of the dosage form.

[0504] Next, the dried dosage form, which had a film weight gain of 6.5%, was overcoated with an immediate-release composition containing 54.0 wt% levodopa, 35.0 wt% carbidopa monohydrate, 10.0 wt% hydroxypropylcellulose, 0.9 wt% aspartame, and 0.1 wt% mint flavor. The immediate-release overcoating composition was added to anhydrous ethanol to form a 10.0 wt% solids suspension. The final dosage form contained 62.5 mg of levodopa and 37.5 mg of carbidopa in the immediate-release coating layer, with 187.5 mg of levodopa contained in the controlled-release drug layer.

[0505] As shown in Figure 18, the release profile of the dosage form shows a rapid release of LD / CD followed by a controlled release with a release duration of approximately 8 hours. The osmotic delivery system can be maintained in the oral cavity for 4-5 hours and then swallowed before eating or maintained in the oral cavity throughout the release period.

[0506] Example 26 Preparation of Controlled Release Platform (37.5 mg CD + 150 mg LD per tablet)

[0507] In this example, the steps of Example 25 were repeated, and the dosage form included a drug layer, an osmotic layer, a film-forming composition, and an outer coating similar to those in Example 25.

[0508] First, a drug layer composition was prepared, comprising 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose, 22.0 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint flavor, and 0.5 wt% of magnesium stearate. The compositions were sieved through a 40-mesh stainless steel sieve and then granulated using a dry granulator to obtain dry granules, which were then mixed with 0.5 wt% of magnesium stearate.

[0509] Next, a second composition, i.e., an osmotic layer, was prepared, comprising 55.0 wt% sodium carboxymethylcellulose 7H4XF, 34.0 wt% sorbitol, 10.0 wt% hydroxypropyl cellulose, and 0.5 wt% red iron oxide; each of these ingredients was passed through a 40-mesh stainless steel sieve and then granulated using a dry granulator to obtain dry granules, which were then mixed with 0.5 wt% of magnesium stearate.

[0510] Next, the drug layer and osmotic layer granules were compressed into a double-layer tablet core. First, 250 mg of the drug layer granules were added to a 9 mm round punch of a tablet press and compacted. Then, 125 mg of the osmotic layer granules were added to the punch and the two layers of granules were compressed into a contact double-layer tablet core using a tablet press.

[0511] Next, the bilayer cores were coated with a film coating. The film-forming composition comprised, by weight, 70% cellulose acetate with an acetyl content of 39.8% and 30% copovidone VA 64. This film-forming composition was dissolved in acetone to form a 4% solids solution. The film-forming composition was sprayed onto the bilayer cores in a Glatt GC 1-pan coater using the process parameters outlined in Example 6 to form a film coating with a film weight gain of 7.0%. Finally, a 0.75 mm exit hole was laser-drilled on the drug layer side of the dosage form.

[0512] Next, the dried dosage form, which had a film weight gain of 7.0%, was overcoated with an immediate-release composition containing 42.8 wt% levodopa, 46.2 wt% carbidopa monohydrate, 10.0 wt% hydroxypropylcellulose, 0.9 wt% aspartame, and 0.1 wt% mint flavor. The immediate-release overcoat composition was added to anhydrous ethanol to form a 10.0 wt% solids suspension. The final dosage form contained 37.5 mg of levodopa and 37.5 mg of carbidopa in the immediate-release coating layer, with 112.5 mg of levodopa contained in the controlled-release drug layer.

[0513] As shown in Figure 19, the release profile of the dosage form shows a rapid release of LD / CD followed by a controlled release with a release duration of approximately 8 hours. The osmotic delivery system can be maintained in the oral cavity for 4-5 hours and then swallowed before eating or maintained in the oral cavity throughout the release period.

[0514] Example 27 Preparation of Controlled Release Platform (37.5 mg CD + 75 mg LD per tablet)

[0515] In this example, the steps of Example 25 were repeated, and the dosage form included a drug layer, an osmotic layer, a film-forming composition, and an outer coating similar to those in Example 25.

[0516] First, a drug layer composition was prepared, comprising 45.0 wt% of levodopa, 31.0 wt% of hydroxypropylcellulose, 22.0 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint flavor, and 0.5 wt% of magnesium stearate. The compositions were sieved through a 40-mesh stainless steel sieve and then granulated using a dry granulator to obtain dry granules, which were then mixed with 0.5 wt% of magnesium stearate.

[0517] Next, a second composition, i.e., an osmotic layer, was prepared, comprising 55.0 wt% sodium carboxymethylcellulose 7H4XF, 34.0 wt% sorbitol, 10.0 wt% hydroxypropyl cellulose, and 0.5 wt% red iron oxide; each of these ingredients was passed through a 40-mesh stainless steel sieve and then granulated using a dry granulator to obtain dry granules, which were then mixed with 0.5 wt% of magnesium stearate.

[0518] Next, the drug layer and osmotic layer granules were compressed into a double-layer tablet core. First, 125 mg of the drug layer granules were added to a 7 mm round punch of a tablet press and compacted. Then, 62.5 mg of the osmotic layer granules were added to the punch and the two layers of granules were compressed into a contact double-layer tablet core using a tablet press.

[0519] Next, the bilayer cores were coated with a film coating. The film-forming composition comprised, by weight, 70% cellulose acetate with an acetyl content of 39.8% and 30% copovidone VA 64. This film-forming composition was dissolved in acetone to form a 4% solids solution. The film-forming composition was sprayed onto the bilayer cores in a Glatt GC 1-pan coater using the process parameters outlined in Example 6 to form a film coating with a film weight gain of 9.0%. Finally, a 0.5 mm exit hole was laser-drilled on the drug layer side of the dosage form.

[0520] Next, the dried dosage form, which had a film weight gain of 9.0%, was overcoated with an immediate-release composition containing 28.2 wt% levodopa, 60.8 wt% carbidopa monohydrate, 10.0 wt% hydroxypropylcellulose, 0.9 wt% aspartame, and 0.1 wt% mint flavor. The immediate-release overcoating composition was added to anhydrous ethanol to form a 10.0 wt% solids suspension. The final dosage form contained 18.75 mg of levodopa and 37.5 mg of carbidopa in the immediate-release coating layer, with 56.25 mg of levodopa contained in the controlled-release drug layer.

[0521] As shown in Figure 20, the release profile of the dosage form shows a rapid release of LD / CD followed by a controlled release with a release duration of approximately 8 hours. The osmotic delivery system can be maintained in the oral cavity for 4-5 hours and then swallowed before eating or maintained in the oral cavity throughout the release period.

[0522] Example 28: Coordination of the Controlled Release Platform and the Retention Platform

[0523] The controlled release platforms (ERP) of Examples 6 to 27 are affixed to the personalized retention platforms (REP) of Examples 1 to 5 to form the disclosed controlled release dosage form (ERP+REP). The controlled release dosage form (ERP+REP) is then affixed to the corresponding teeth in the oral cavity. The controlled release dosage form (ERP+REP) can remain in the oral cavity until the push layer reaches the delivery port, or remain there for 4-24 hours. The controlled release dosage form (ERP+REP) is removed, the controlled release platform (ERP) is replaced, and the controlled release dosage form (ERP+REP) is re-fixed to the corresponding teeth in the oral cavity to continue drug release.

[0524] Example 29 Preparation of Controlled Release Platform and Its Coordination with Retention Platform (Each Tablet Contains 62.5 mg CD + 250 mg LD)

[0525] In this example, the steps of Example 9 were repeated to provide a dosage form. In this example, a dry dosage form with a 4.8% film weight gain was overcoated with an immediate-release composition comprising 23.78 wt% LD, 64.22 wt% CD, 10.0 wt% hydroxypropylcellulose, and 1.0 wt% aspartame (as shown in FIG3 c). The immediate-release overcoat composition was added to ethanol to form a 6.7% solids suspension. The final controlled-release platform ERP dosage form comprised an immediate-release coating layer containing 62.5 mg CD and 25 mg LD, with 225 mg LD contained in a controlled-release drug layer.

[0526] The controlled-release platform (ERP) is fixed to the personalized retention platform (REP) to form the controlled-release dosage form (ERP+REP) disclosed herein. The controlled-release dosage form (ERP+REP) is then fixed to the corresponding teeth in the oral cavity. The controlled-release dosage form (ERP+REP) can remain in the oral cavity until the push layer reaches the delivery port, or remain there for 8 hours. The controlled-release dosage form (ERP+REP) is removed, the controlled-release platform (ERP) is replaced, and the controlled-release dosage form (ERP+REP) is re-fixed to the corresponding teeth in the oral cavity to continue drug release.

[0527] The release profile of the controlled-release dosage form (ERP+REP) was measured in 0.1N aqueous hydrochloric acid using the USPI basket method. As shown in Figure 21, the controlled-release dosage form (ERP+REP) with a 4.8% increase in film weight delivered LD at an average rate of 27.6 mg / hr, 85% of LD was delivered within 7.7 hours, and 85% of CD was delivered within 1 hour.

[0528] Although the specific embodiments of the present disclosure have been described above, those skilled in the art will appreciate that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present disclosure. Therefore, the scope of protection of the present disclosure is defined by the appended claims.

[0529] Example 30 Cobalt-chromium alloy rear-insertion oral retention device

[0530] In the embodiment shown in FIG22 , the post-insertion oral retention device for tablets is composed of a tooth-fitting component 11 and a drug-carrying component 41 connected together. The tooth-fitting component 11 can fit snugly against the teeth in the subject's mouth, and the drug-carrying component 41 is sized to accommodate at least one tablet and retain the tablet in the mouth. Both the tooth-fitting component 11 and the drug-carrying component 41 are made of a cobalt-chromium alloy, and the tooth-fitting component 11 and the drug-carrying component 41 are connected at their respective sides. The drug-carrying component includes a ring body 31 and a stopper 21 at its end. The ring body 31 is a circular closed loop with an opening 311 for inserting a tablet. The stopper is spaced apart from the ring body and each is connected to the tooth-fitting component 11. In another embodiment, the stopper can be integrally formed with the ring body and then fixed to the tooth-fitting component, or it can be integrally formed with the ring body and the tooth-fitting component. After the oral retention device is matched with the teeth in the subject's mouth via the tooth-fitting member, the opening 311 opens toward the molars in the horizontal direction formed by the molars and incisors (the ring body 31 is located on the molar side of the horizontal direction, i.e., the position of the ring body 31 is closer to the molars than the position of the stopper 21), and the tablet is inserted from the molars toward the incisors in the horizontal direction. The stopper is a circular, hollow arc shape, and its structure is used to confine the tablet to the drug-carrying member. The tooth-fitting member 11 fits with the mandibular first molar, second molar, and / or third molar in the subject's mouth, enveloping the teeth through the fit.

[0531] When the oral retention device of this embodiment is worn in the oral cavity after loading the tablet, the tablet can be firmly fixed and will not slip out of the device even if the rapid-release drug layer is quickly dissolved by intense mouthwash.

[0532] Example 31 Cobalt-chromium alloy front-insertion oral retention device

[0533] In the embodiment shown in Figure 23, the tablet front-insertion oral retention device is composed of a tooth-fitting component 12 and a drug-carrying component 42 connected together. The tooth-fitting component 12 can fit snugly against the teeth in the subject's mouth, and the drug-carrying component 42 is sized to accommodate at least one tablet and retain it in the mouth. Both the tooth-fitting component 12 and the drug-carrying component 42 are made of cobalt-chromium alloy, and are connected to each other at their respective sides. The drug-carrying component 42 includes a ring body 32 and a stopper 22 at its end. The ring body 32 is a circular, closed loop with an opening 321 for inserting a tablet. The stopper is spaced apart from the ring body and each is connected to the tooth-fitting component 12. In another embodiment, the stopper can be integrally formed with the ring body and then fixed to the tooth-fitting component, or it can be integrally formed with the ring body and the tooth-fitting component. The opening 321 opens toward the incisors in the horizontal direction formed by the molars and incisors (the ring body 32 is located on the side of the incisors in the horizontal direction formed by the molars and incisors, that is, the position of the ring body 32 is closer to the incisors than the position of the limiter 22). The tablet is inserted from the incisors to the molars in the horizontal direction formed by the molars and incisors. The limiter is a hollow arc shape, and the structure of the limiter is used to confine the tablet to the drug-carrying member. The tooth-fitting member 12 fits with the mandibular first molar, second molar, and / or third molar in the subject's mouth, wrapping the teeth through the fit.

[0534] After the oral retention device of this embodiment is worn in the mouth and loaded with tablets, the tablets may slip out of the device during the rapid dissolution of the drug rapid-release layer after vigorous mouthwash. The tablets may also slip out of the device during wearing. However, the device still has certain use value.

[0535] Example 32 3D printing preparation of cobalt-chromium alloy rear-insertion oral retention device

[0536] The preparation method of the cobalt-chromium alloy rear-insertion oral retention device of this embodiment comprises the following steps:

[0537] Step 1: Scan the tablet's dimensional data using the 3Shape Dental System scanner. Next, design the drug-carrying component that holds the medication using SolidWorks software, create and save it as a "standard attachment" file. Each time you design a mouth-retention device in 3Shape Dental System, add the "standard attachment" and assemble it with the dental anastomotic component to create a complete mouth-retention device.

[0538] Step 2: Perform an intraoral scan:

[0539] a. Open Trios Scan software;

[0540] b. Create new patients, create new cases, and confirm;

[0541] c. Select the research model;

[0542] d. Use Trios oral scanner to scan the mandible;

[0543] e. Perform maxillary scan;

[0544] f. Perform occlusal scan;

[0545] g. Post-process the file to confirm that the scanned data of all molars and premolars are complete and free of defects. The upper and lower teeth occlusion scan is accurate;

[0546] h. Save the file in 3OXZ or STL format.

[0547] Step 3: Device Design

[0548] a. Open 3Shape Dental System software;

[0549] b. Create a new order;

[0550] c. Select the tooth position;

[0551] d. Select the coping design;

[0552] e. Import oral scan tooth data (STL file);

[0553] f. Add "standard accessories" and assemble with the tooth-matching components to form an integrated oral retention device, with the opening facing the molars in the horizontal direction formed by the molars and incisors, so that the tablet can be inserted from the molars to the incisors in the horizontal direction formed by the molars and incisors.

[0554] g. After the design is completed, export it to 3OXZ or STL format file.

[0555] Step 4: 3D Printing / Polishing in Place.

[0556] a.CAM program input;

[0557] b. Turn on the EOS laser deposition equipment;

[0558] c. Preparation of cobalt-chromium alloy metal powder;

[0559] d. Download the processing program of the product to be produced;

[0560] e. Click to start processing;

[0561] f. After processing is completed, open the door to vacuum and clean;

[0562] g. Take out the device and put it into place / grind and polish it. The device is shown in Figure 1.

[0563] As shown in Figure 22, the cobalt-chromium alloy back-insert oral retention device prepared in this embodiment includes a tooth-fitting component 11 and a drug-carrying component. The tooth-fitting component 11 and the drug-carrying component are connected at their respective sides. The tooth-fitting component can fit tightly against teeth in the oral cavity. The drug-carrying component can hold at least one tablet and retain it in the oral cavity. The tablet can be a controlled-release preparation, preferably an osmotic pump tablet. The osmotic pump tablet contains an active drug and excipients. The active drug is one of levodopa or its ester, carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin, or one or both of levodopa or its ester and carbidopa. The drug-carrying component has a circular closed loop cross-section. The drug-carrying component can have a mesh or non-mesh structure. The drug-carrying component includes at least one ring body 31 and at least one stopper 21 at its end. The ring body 31 defines an opening 311 for tablet insertion. The stopper is a circular, hollow arc shape. The opening faces the molars in a horizontal direction formed by the molars and the incisors, and the tablet is inserted from the molars toward the incisors in the horizontal direction.

[0564] Example 33 Preparation of Injection Molded Cobalt-Chromium Alloy Oral Retention Device

[0565] First, a plaster model of the patient's / volunteer's teeth was prepared using traditional molding techniques. Then, a dental wax model was manually prepared on the plaster model using traditional manual techniques using dental wax. Finally, an oral retention device was prepared using cobalt-chromium porcelain alloy using traditional injection molding.

[0566] Example 34: Cobalt-chromium alloy front-insertion oral retention device prepared by 3D printing

[0567] The oral retention device shown in Figure 23 is prepared using the same method as in Example 32, except that in step 3f, the positions of the ring body and the stopper of the drug-carrying member are opposite to those in Example 32. Ring body 32 of drug-carrying member 42 forms an opening 321 for tablet insertion. The opening opens toward the incisors in the horizontal direction formed by the molars and incisors, and the tablet is inserted from the incisors toward the molars in this horizontal direction. The tablet can be a controlled-release formulation, preferably an osmotic pump tablet.

[0568] Example 35

[0569] This embodiment is an oral medication dispenser that covers all mandibular teeth, as shown in Figure 24. It includes a core component 1 and a fixture 2, which is a fixture. The core component 1 is schematically shown in Figure 25, the fixture 2 is schematically shown in Figure 26, and a cross-sectional view of the oral medication dispenser is shown in Figure 27. The lingual side 201, buccal side 202, and occlusal surface 203 of the fixture correspond to the lingual, buccal, and occlusal surfaces of the teeth and cover the outer circumference of the teeth; the fixture 2 also covers the molar-fitting functional area 11. The core component 1 consists of the molar-fitting functional area 11 and the drug-carrying functional area 12. The molar-fitting functional area 11 can fit tightly with the mandibular first and second premolars and first and second molars in the subject's oral cavity. The drug-carrying functional area 12 is sized to accommodate at least one tablet and secure the tablet in the oral cavity. The fixture 2 fits tightly with all of the subject's mandibular teeth and the molar-fitting functional area 11, securing the core component 1 and the tablet in the oral cavity. The molar anastomosis functional area 11 and the drug-carrying functional area 12 are made of cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-carrying functional area 12 are connected at their respective sides. The drug-carrying functional area 12 includes a first ring 121 and a second ring 122, and the first ring 121 and the second ring 122 are circular closed rings. The tablet is inserted from the second ring 122 and is blocked by the first ring 121. The molar anastomosis functional area 11 and the fixing device 2 are combined in an embedded mechanical assembly manner, and a slot is provided on the fixing device 2 at a position corresponding to the drug-carrying functional area 12 to achieve detachable fixation of the fixing device 2 and the core component 1. The fixing device 2 is made of colorless and transparent polyethylene terephthalate and covers all mandibular teeth, that is, covers 14 teeth. After the core component 1 and the fixing device 2 are combined, they match the teeth in the subject's mouth.

[0570] The oral applicator of this embodiment can be worn firmly in the oral cavity after being loaded with tablets, and the tablets are fixed in the oral cavity. The retainer, core component and tablets will not fall off or shift with the movement of the oral cavity. It is very comfortable to wear and has little impact on facial appearance.

[0571] Example 36

[0572] The present embodiment is an oral applicator covering 10 mandibular teeth, as shown in Figure 28, which includes a core component 1 and a fixing device 2, the fixing device 2 is a fixer, and the core component 1 is composed of a molar anastomosis functional area 11 and a drug-carrying functional area 12. The molar anastomosis functional area 11 can be tightly fitted with the mandibular first and second premolars and the first and second molars in the subject's oral cavity, and the size of the drug-carrying functional area 12 is such that it can accommodate at least one tablet and fix the tablet in the oral cavity. The fixing device 2 is tightly fitted with part of the subject's mandibular teeth (including the teeth from the left canine to the right second molar), and is tightly fitted with the molar anastomosis functional area 11, so that the core component 1 and the tablet are fixed in the oral cavity. The molar anastomosis functional area 11 and the drug-carrying functional area 12 are made of cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-carrying functional area 12 are connected at their respective sides. The drug-carrying functional area 12 includes a first ring 121 and a second ring 122. The first ring 121 and the second ring 122 are elliptical closed rings. A pair of clamping walls 123 are symmetrically provided on the first ring 121 along the direction of the open end of the molar anastomosis functional area, which is suitable for the insertion of non-cylindrical tablets. The tablets are inserted from the second ring 122 and are blocked by the first ring 121. The molar anastomosis functional area 11 and the fixture 2 are combined in an embedded mechanical assembly manner. Slots are provided on the fixture 2 at positions corresponding to the drug-carrying functional area 12 to achieve detachable fixation of the fixture 2 and the core component 1. The fixture 2 is made of colorless and transparent polyethylene terephthalate and covers 10 teeth in the mandible from the left canine to the right second molar. After the core component 1 and the fixture 2 are combined, they match part of the mandibular teeth in the subject's mouth.

[0573] The oral applicator of this embodiment can be worn firmly in the oral cavity after being loaded with tablets, and the tablets are fixed in the oral cavity. The retainer, core component and tablets will not fall off or shift with the movement of the oral cavity. It is very comfortable to wear and has little impact on facial appearance.

[0574] Example 37

[0575] The present embodiment is an oral medication device that covers 7 mandibular teeth, as shown in Figure 29, which includes a core component 1 and a fixing device 2, the fixing device 2 is a fixer, and the core component 1 is composed of a molar anastomosis functional area 11 and a drug-carrying functional area 12. The molar anastomosis functional area 11 can be tightly fitted with the mandibular first and second premolars and the first and second molars in the subject's oral cavity, and the size of the drug-carrying functional area 12 is such that it can accommodate at least one tablet and fix the tablet in the oral cavity. The fixing device 2 is tightly fitted with part of the subject's mandibular teeth (including a total of 7 teeth from the right incisor to the right second molar), and is tightly fitted with the molar anastomosis functional area 11, so that the core component 1 and the tablet are fixed in the oral cavity. The molar anastomosis functional area 11 and the drug-carrying functional area 12 are made of cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-carrying functional area 12 are connected at their respective sides. The drug-carrying functional area 12 includes a first ring 121 and a second ring 122. The first ring 121 and the second ring 122 are circular closed rings, which are suitable for inserting cylindrical tablets. The tablets are inserted from the second ring 122 and are blocked by the first ring 121. The molar anastomosis functional area 11 and the fixture 2 are combined in an embedded mechanical assembly manner. Slots are provided on the fixture 2 at positions corresponding to the drug-carrying functional area 12 to achieve detachable fixation of the fixture 2 and the core component 1. The fixture 2 is made of colorless and transparent ethylene-vinyl acetate copolymer and covers a total of 7 teeth on the right side of the mandible from the incisor to the second molar. The core component 1 and the fixture 2 are combined to match the teeth of the subject.

[0576] When the oral applicator of this embodiment is worn in the mouth, the tablets can be fixed in the mouth after being loaded and are not easy to fall off. The wearing firmness is not significantly different from that of Examples 35 and 36. At the same time, because the number of teeth covered is small, the wearing comfort and the impact on facial appearance are better than those of Examples 35 and 36.

[0577] Example 38

[0578] The difference between this embodiment and Example 35 is that the oral applicator covers all maxillary teeth, and the molar anastomosis functional area 11 can fit tightly with the maxillary second premolar and the first, second and third molars in the subject's mouth. The rest is the same as Example 35.

[0579] The oral applicator of this embodiment can be worn firmly in the oral cavity after being loaded with tablets, and the tablets are fixed in the oral cavity. The retainer, core component and tablets will not fall off or shift with the movement of the oral cavity. It is very comfortable to wear and has little impact on facial appearance.

[0580] Example 39

[0581] The difference between this embodiment and Example 35 is that the core component 1 is 3 teeth long and can be designed for subjects with molar defects; the first ring 121 and the second ring 122 are polygonal closed loops, and the molar anastomotic functional area 11 and the fixing device 2 are bonded together using a pressure-sensitive adhesive as an adhesive, and the bonding position is the entire outer surface of the molar anastomotic functional area 11, and the adhesive thickness is 0.1 mm; the fixing device 2 is made of colorless and transparent ethylene-vinyl acetate copolymer; the rest is the same as Example 35.

[0582] The oral applicator of this embodiment can be worn firmly in the oral cavity after being loaded with tablets, and the tablets are fixed in the oral cavity. The retainer, core component and tablets will not fall off or shift with the movement of the oral cavity. It is very comfortable to wear and has little impact on facial appearance.

[0583] Example 40

[0584] The structural schematic diagram of the oral medication dispenser of this embodiment is shown in Figure 30 . It includes a core component 1 and a fixing device 2, which serves as a fixing layer. A cross-sectional view of the oral medication dispenser is shown in Figure 31 . The core component 1 comprises a molar-fitting functional area 11 and a drug-carrying functional area 12. The molar-fitting functional area 11 is designed to fit snugly against the mandibular first and second premolars and first and second molars in the subject's oral cavity. The drug-carrying functional area includes a first ring 121 and a second ring 122. The first and second rings 121 and 122 are circular, closed loops suitable for inserting cylindrical tablets. Tablets are inserted through the second ring 122 and are blocked by the first ring 121. The drug-carrying functional area 12 is sized to accommodate at least one tablet and secure it in the oral cavity. The fixing device 2 is attached to the entire outer surface of the first and second segments of the U-shaped structure. The molar-fitting functional area 11 and the drug-carrying functional area 12 are made of cobalt-chromium alloy and are connected at their respective sides. Fixture 2 is made of colorless, transparent polyethylene terephthalate, which is softened by heating and then applied to the surface of the molar anastomotic functional area 11. Excess material is trimmed after cooling. Fixture 2 is 0.3-0.5mm thick. The core assembly 1 and fixture 2 are combined to match the subject's teeth.

[0585] The oral applicator of this embodiment can be worn firmly in the oral cavity after being loaded with tablets, and the tablets are fixed in the oral cavity. The fixing layer, core component and tablets will not fall off or shift with the movement of the oral cavity. It is very comfortable to wear and has little impact on the facial appearance.

[0586] Example 41

[0587] The difference between this embodiment and embodiment 40 is that the fixing device 2 is light blue polycaprolactone and the thickness of the fixing device 2 is 0.8-1 mm. The rest is the same as embodiment 40.

[0588] The oral applicator of this embodiment can be worn more firmly in the oral cavity after being loaded with tablets, and the tablets can be fixed in the oral cavity. However, because the fixing device is thicker, the oral applicator of this embodiment is not as firmly worn and comfortable as that of Example 40. Compared with Example 40, this embodiment has a greater impact on facial appearance.

[0589] Example 42

[0590] The difference between this embodiment and embodiment 40 is that the core component 1 and the fixing device 2 are bonded together using pressure-sensitive adhesive, the bonding position is the part where the molar anastomotic functional area contacts the teeth, and the thickness of the adhesive is 0.1 mm; the fixing device 2 is a colorless and transparent polypropylene film with a thickness of 0.02-0.04 mm; the rest is the same as embodiment 40.

[0591] The oral applicator of this embodiment can be worn firmly in the oral cavity after being loaded with tablets, and the tablets can be fixed in the oral cavity. However, because the thickness of the fixing layer is thin and the surface of the fixing layer material is smooth, the oral applicator of this embodiment is not as firm and comfortable to wear as in Examples 40 and 41.

[0592] Example 43

[0593] The oral drug delivery device of this embodiment is shown in Figure 32, which includes a core component 1 and a fixing device 2 that are symmetrical on the left and right sides. The fixing device 2 is a fixer. The two core components 1 are composed of a molar anastomosis functional area 11 and a drug-carrying functional area 12. The molar anastomosis functional area 11 can be tightly fitted with the maxillary first and second premolars and the first and second molars in the subject's oral cavity. The size of the drug-carrying functional area 12 is such that it can accommodate at least one tablet and fix the tablet in the oral cavity. The fixing device 2 is tightly fitted with all the maxillary teeth of the subject and with the molar anastomosis functional area 11, so that the core component 1 and the tablet are fixed in the oral cavity. The molar anastomosis functional area 11 and the drug-carrying functional area 12 are made of cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-carrying functional area 12 are connected at their respective sides. The drug-carrying functional area 12 includes a first ring 121 and a second ring 122. The first ring 121 and the second ring 122 are circular closed rings, which are suitable for inserting cylindrical tablets. The tablets are inserted from the second ring 122 and are blocked by the first ring 121. The molar anastomosis functional area 11 and the fixture 2 are combined in an embedded mechanical assembly manner. Slots are provided on the fixture 2 at positions corresponding to the drug-carrying functional area 12 to achieve detachable fixation of the fixture 2 and the core component 1. The fixture 2 is made of colorless and transparent polyethylene terephthalate and covers all maxillary teeth. After the core component 1 and the fixture 2 are combined, they match the teeth in the subject's mouth.

[0594] The oral applicator of this embodiment can be worn firmly in the oral cavity after being loaded with tablets, and the tablets are fixed in the oral cavity. The retainer, core component and tablets will not fall off or shift with the movement of the oral cavity. It is very comfortable to wear and has little impact on facial appearance.

[0595] Example 44

[0596] The cobalt-chromium alloy core component was prepared by laser melting and casting, and the fixator was prepared by die-casting. The specific steps are as follows:

[0597] Step 1: Obtain the subject's oral data by scanning the subject's oral cavity or taking a plaster model of the oral cavity and then scanning it.

[0598] Step 2: Use 3D design software and dental design software to respectively design the drug-loading functional area and molar anastomosis functional area of ​​the core component, and combine them in the dental design software to generate the core component design file.

[0599] Step 3: Prepare the cobalt-chromium alloy core components through laser melting, grinding, polishing and cleaning.

[0600] Step 4: Wear the core component on the subject's dental mold, heat and soften the polyethylene terephthalate through a laminator, and then vacuum it on the dental mold. Trim off excess material and polish it. Remove it from the dental mold to obtain the oral applicator, which matches the subject's teeth.

[0601] Example 45

[0602] The cobalt-chromium alloy core components were prepared by injection molding and the applicator was prepared by die-casting. The specific steps are as follows:

[0603] Step 1: Make a plaster model by taking a mouth mold of the subject.

[0604] Step 2: Use dental wax as material to prepare a dental wax model on the plaster model.

[0605] Step 3: Use cobalt-chromium ceramic alloy as the material and prepare the core components through traditional injection molding process.

[0606] Step 4: Wear the core component on the plaster dental model, heat and soften the polyurethane through a laminating machine, and then vacuum the dental model. Trim away excess material and polish it. Remove it from the dental model to obtain the oral applicator consisting of the core component and the retainer.

[0607] Example 46

[0608] The cobalt-chromium alloy core component was prepared by injection molding and the applicator was prepared by the impression method. The specific steps are as follows:

[0609] Step 1: Make a plaster model by taking a mouth mold of the subject.

[0610] Step 2: Use dental wax as material to prepare a dental wax model on the plaster model.

[0611] Step 3: Using cobalt-chromium porcelain alloy as the material, prepare the applicator through traditional injection molding process.

[0612] Step 4: Wear the core component on the corresponding teeth of the subject, heat and soften the polycaprolactone material, and cover the molar matching functional area of ​​the subject's teeth and the core component. After cooling, remove it from the teeth together with the core component to obtain the oral applicator.

[0613] Comparative Example 1

[0614] The oral medicator of this comparative example only includes the core component 1 in Example 35, as shown in FIG25 .

[0615] Effect Example 1

[0616] The oral applicators of Example 35, Example 37, Example 40 and Comparative Example 1 were tested for wearing firmness, and the wearing firmness scores were as follows in Table 2: 1 point means not firm, and the applicator is very easy to fall off during basic oral movements such as opening the mouth and talking after wearing; 2 point means relatively loose, tilted or fell off during basic oral movements such as opening the mouth and talking after wearing; 3 point means basically firm, and the applicator is easy to fall off only during large-scale oral movements; 4 point means firm, and the applicator tilts or loosens only during large-scale oral movements, but does not fall off; 5 point means very firm, and the applicator does not loosen, tilt or fall off during basic or large-scale oral movements.

[0617] Table 2

[0618] As can be seen from Table 2, Examples 35, 37 and 40 of the present application adopt a combination of a fixing device and a core component, and the wearing security is better compared with the comparative example 1 which only adopts the core component, and the wearing security is higher when the fixing device adopts a fixer than when the fixing layer is adopted.

[0619] Effect Example 2

[0620] The oral applicators of Example 35, Example 37, Example 40 and Comparative Example 1 were tested for wearing comfort, and the wearing comfort scores were as follows in Table 3: 1 point means extremely uncomfortable, with obvious foreign body sensation or irritation, and unacceptable; 2 points means uncomfortable, with obvious foreign body sensation or irritation, and not very acceptable; 3 points means there is a foreign body sensation or irritation, which has a slight effect on oral function, but is acceptable; 4 points means a high degree of comfort, with no obvious foreign body sensation or irritation, and basically no effect on oral function; 5 points means a high degree of comfort, with almost no foreign body sensation or irritation, and no effect on oral function.

[0621] Table 3

[0622] As can be seen from Table 3, Examples 35, 37 and 40 of the present application adopt a combination of a fixing device and a core component, and are more comfortable to wear than Comparative Example 1 which only uses a core component.

[0623] Effect Example 3

[0624] The degree of influence of the oral applicators of Example 35, Example 37, Example 40 and Comparative Example 1 on facial appearance when worn was tested, and the scores were as shown in Table 4 below: 1 point means the degree of influence on facial appearance is the greatest and unacceptable; 2 points means the degree of influence on facial appearance is relatively large and not quite acceptable; 3 points means there is an influence on facial appearance, but it is acceptable; 4 points means the influence on facial appearance is small; and 5 points means there is almost no difference in facial appearance before and after wearing.

[0625] Table 4

[0626] It can be seen from Table 4 above that, compared with Example 1 which only uses the core component, the oral applicator of Examples 35, 37 and 40 of the present application, which combines the fixing device and the core component, has a similar degree of impact on the facial appearance when worn, that is, the oral applicator of the embodiment of the present application has a similar wearing aesthetics as the comparative example.

[0627] The coating films used in the following examples and comparative examples have a tensile strength of approximately 1-10 MPa, an elongation at break of approximately 1.1-2.0, and an average thickness of approximately 100±8 μm to 200±10 μm. The hydroxypropyl cellulose having a weight-average molecular weight of 80,000 may be hydroxypropyl cellulose EXF, having a Brookfield viscosity of approximately 300-600 mPa·s and a concentration of approximately 10%.

[0628] Example 47 Preparation of Osmotic Pump Tablets

[0629] The osmotic pump tablets of this embodiment use levodopa as the active pharmaceutical ingredient and are prepared according to the following steps:

[0630] (1) Preparation of drug-containing layer

[0631] Based on the total weight of the drug-containing layer, 63.0 wt% of levodopa, 10.0 wt% of hydroxypropyl cellulose with a weight-average molecular weight of 80,000, 5.0 wt% of povidone (K29 / 32), 10.0 wt% of poloxamer (P407), 10.0 wt% of sorbitol, 0.9 wt% of aspartame, 0.1 wt% of mint flavor, and 0.5 wt% of magnesium stearate are taken. Each of the above ingredients is passed through a 40-mesh stainless steel sieve and then dry granulated. The granules are then sieved through a 1.2 mm stainless steel sieve and then mixed with 0.5 wt% of magnesium stearate to obtain drug-containing layer granules.

[0632] (2) Preparation of boost layer

[0633] Based on the total weight of the push layer, 49.0wt% sodium carboxymethyl cellulose (7H4XF), 30.0wt% sorbitol, 20.0wt% hydroxypropyl cellulose (EXF) and 0.5wt% red iron oxide are taken; each of the above ingredients is passed through a 40-mesh stainless steel sieve and then dry granulated; the granules are sieved through a 1.2mm stainless steel sieve and then mixed with 0.5wt% magnesium stearate to obtain the push layer particles.

[0634] (3) Preparation of double-layer tablet core

[0635] The drug-layer granules and the push-layer granules were compressed into bilayer tablet cores using a 21 x 9.5 mm capsule-shaped punch. 1047.6 mg of the drug-layer granules were added to the punch and compacted. Then, 360 mg of the push-layer granules were added to the punch. The two layers of granules were compressed into contacting bilayer tablet cores. The final bilayer tablet cores contained approximately 660 mg of levodopa.

[0636] (4) Preparation of osmotic pump tablets

[0637] The bilayer tablet core is wrapped with a coating film. The raw material composition of the coating film comprises, by weight percentage, 55 wt% cellulose acetate and 45 wt% copovidone VA 64, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% acetyl groups. The composition is dissolved in acetone to form a 4% solution. The solution is sprayed onto the bilayer tablet core using a pan coating machine to form a coating film, thereby obtaining an osmotic pump tablet. Based on the resulting bilayer osmotic pump tablet, the coating film content is 6.5 wt%. A 1.0 mm drug release hole is drilled in the coating film using a laser or a machine.

[0638] The release profile of the final dosage form was measured in simulated saliva using the USPI paddle plate method. Figure 33 depicts the release profile of LD. The osmotic pump tablet of this example can be maintained in the oral cavity, releasing 85% of the active drug from the tablet for approximately 8 hours. The released drug in the oral cavity is then continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentrations. The retention of the active drug ingredient at the release site is less than 10%.

[0639] Example 48 Preparation of Osmotic Pump Tablets

[0640] The operation of Example 47 was repeated in this example, except that:

[0641] (1) The weight of the drug-containing layer is 1309.5 mg, the weight of the booster layer is 451.6 mg, and the tableting die is a 21*12 mm capsule punch.

[0642] (2) The coating film comprises 50 wt% of cellulose acetate film and 50 wt% of copovidone VA 64. Based on the obtained osmotic pump tablet, the content of the coating film is 6.0 wt%.

[0643] The release profile of the final dosage form was measured in simulated saliva using the USPI paddle plate method. Figure 34 depicts the release profile of LD. The osmotic pump tablet of this example can be maintained in the oral cavity, releasing 85% of the active drug from the tablet for approximately 8 hours. The released drug in the oral cavity is then continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood concentrations. The retention of the active drug ingredient at the release site is less than 10%.

[0644] Example 49 Preparation of Osmotic Pump Tablets;

[0645] The osmotic pump tablet of this embodiment uses levodopa as the active pharmaceutical ingredient. The procedure of Example 47 is repeated in this embodiment, except that:

[0646] (1) Preparation of drug-containing layer

[0647] Based on the total mass of the drug-containing layer, 58.0 wt% of levodopa, 15.0 wt% of hydroxypropyl cellulose with a weight-average molecular weight of 80,000, 5.0 wt% of povidone (K29 / 32), 5.0 wt% of poloxamer (P407), 15.0 wt% of sorbitol, 0.9 wt% of aspartame, and 0.1 wt% of mint flavor are taken. Each of the above ingredients is passed through a 40-mesh stainless steel sieve, then wet granulated, and fluidized bed dried; the granules are sieved through a 1.2 mm stainless steel sieve, and then mixed with 1.0 wt% of magnesium stearate to obtain drug-containing layer granules.

[0648] (2) Preparation of boost layer

[0649] Based on the total weight of the push layer, 68.5wt% sodium carboxymethyl cellulose (7H4XF), 10.0wt% sorbitol, 20.0wt% hydroxypropyl cellulose (EXF) and 0.5wt% red iron oxide are taken; each of the above ingredients is passed through a 40-mesh stainless steel sieve and then dry granulated; the granules are sieved through a 1.2mm stainless steel sieve and then mixed with 0.5wt% colloidal silicon dioxide and 0.5wt% magnesium stearate to obtain push layer particles.

[0650] (3) Preparation of double-layer tablet cores and osmotic pump tablets

[0651] The drug-containing layer weighed 1484.1 mg, the booster layer weighed 510 mg, and the tableting die used a 21 x 12 mm capsule punch. The coating consisted of 60 wt% cellulose acetate and 40 wt% copovidone VA64. Based on the resulting bilayer osmotic pump tablets, the coating content was 6.5 wt%.

[0652] The release profile of the final dosage form was measured in simulated saliva using the USPI slurry plate method. The osmotic pump tablet was combined with the oral retention device of Example 30 and fixed to the teeth in the oral cavity. Figure 35 depicts the release profile of LD. 85% of the active drug in the osmotic pump tablet was released over a period of approximately 16 hours. The drug released in the oral cavity was continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentration. The retention of the active drug ingredient at the release site was less than 10%.

[0653] Example 50 Preparation of Osmotic Pump Tablets

[0654] This example was prepared according to the following steps:

[0655] (1) Preparation of drug-containing layer

[0656] Based on the total weight of the drug-containing layer, 58.0 wt% of levodopa, 15.0 wt% of hydroxypropyl cellulose with a weight-average molecular weight of 80,000, 5.0 wt% of povidone (K29 / 32), 5.0 wt% of poloxamer (P407), 15.0 wt% of sorbitol, 0.9 wt% of aspartame, and 0.1 wt% of mint flavor are taken. Each of the above ingredients is passed through a 40-mesh stainless steel sieve, then wet granulated and fluidized bed dried; the granules are sieved through a 1.2 mm stainless steel sieve, and then mixed with 1.0 wt% of magnesium stearate to obtain drug-containing layer granules.

[0657] (2) Preparation of boost layer

[0658] Based on the total weight of the push layer, 68.5wt% sodium carboxymethyl cellulose (7H4XF), 10.0wt% sorbitol, 20.0wt% hydroxypropyl cellulose (EXF) and 0.5wt% red iron oxide are taken; each of the above ingredients is passed through a 40-mesh stainless steel sieve and then dry granulated; the granules are sieved through a 1.2mm stainless steel sieve and then mixed with 0.5wt% colloidal silicon dioxide and 0.5wt% magnesium stearate to obtain push layer particles.

[0659] (3) Preparation of double-layer tablet core

[0660] The drug-containing layer and push-layer granules were compressed into bilayer tablet cores using a 7.5 mm round punch. 758.6 mg of drug-containing layer granules were added to the punch and compacted. Then, 379.3 mg of push-layer granules were added to the punch. The two layers were compressed into contact bilayer tablet cores. The final bilayer tablets contained 440 mg of levodopa.

[0661] (4) Preparation of osmotic pump tablets

[0662] The bilayer tablet core is wrapped with a coating film. The raw material composition of the coating film comprises, by weight percentage, 50 wt% cellulose acetate, 5 wt% polyethylene glycol 400, and 45 wt% copovidone VA 64, wherein the cellulose acetate is a cellulose acetate film containing 39.8 wt% acetyl groups. The raw material composition of the coating film is dissolved in acetone to form a 4% solution. This solution is sprayed onto the bilayer tablet core using a pan coating machine to form a coating film, thereby obtaining an osmotic pump tablet. Based on the resulting osmotic pump tablet, the coating film content is 4.5 wt%. A 1.0 mm drug release hole is drilled in the coating film using a laser or a machine.

[0663] The release profile of the final dosage form was measured in simulated saliva using the USPI paddle plate method. Figure 36 depicts the release profile of LD. The osmotic pump tablet of this example can be maintained in the oral cavity, releasing 85% of the active drug from the tablet for approximately 5 hours. The released drug in the oral cavity is then continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentrations. The retention of the active drug ingredient at the release site is less than 10%.

[0664] Example 51 Preparation of Osmotic Pump Tablets;

[0665] In this example, the procedure of Example 50 was repeated, except that the weight of the drug-containing layer was 569.2 mg, the weight of the booster layer was 284.6 mg, and the tableting die was a 7 mm round punch. Based on the resulting bilayer osmotic pump tablets, the coating film content was 6.0 wt%.

[0666] The release profile of the final dosage form was measured in simulated saliva using the USPI slurry plate method. The osmotic pump tablet was combined with the oral retention device of Example 30 and fixed to the teeth in the oral cavity. Figure 37 depicts the release profile of LD. 85% of the active drug in the osmotic pump tablet was released over a period of approximately 5 hours. The drug released in the oral cavity was continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentrations. The retention of the active drug ingredient at the release site was less than 10%.

[0667] Example 52 Preparation of Osmotic Pump Tablets

[0668] In this example, the procedure of Example 50 was repeated, except that the weight of the drug-containing layer was 379.3 mg, the weight of the booster layer was 189.7 mg, and the tableting die was a 6 mm round punch. Based on the resulting bilayer osmotic pump tablets, the coating film content was 9.0 wt%.

[0669] The release profile of the final dosage form was measured in simulated saliva using the USPI slurry plate method. Figure 38 depicts the release profile of LD. The osmotic pump tablet was combined with the oral retention device of Example 30 and fixed to the teeth that match the oral cavity. 85% of the active drug in the osmotic pump tablet was released over a period of approximately 5 hours. The drug released in the oral cavity was continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentration. The retention of the active drug ingredient at the release site was less than 10%.

[0670] Example 53 Preparation of Osmotic Pump Tablets;

[0671] The osmotic pump tablet of this embodiment is prepared according to the following steps:

[0672] (1) Preparation of drug-containing layer

[0673] Based on the total weight of the drug-containing layer, 58.0 wt% of levodopa, 15.0 wt% of hydroxypropyl cellulose with a weight-average molecular weight of 80,000, 5.0 wt% of povidone (K29 / 32), 5.0 wt% of poloxamer (P407), 15.0 wt% of sorbitol, 0.9 wt% of aspartame, and 0.1 wt% of mint flavor are taken. Each of the above ingredients is passed through a 40-mesh stainless steel sieve, then wet granulated and fluidized bed dried; the granules are sieved through a 1.2 mm stainless steel sieve, and then mixed with 1.0 wt% of magnesium stearate to obtain drug-containing layer granules.

[0674] (2) Preparation of boost layer

[0675] Based on the total weight of the push layer, 68.5wt% sodium carboxymethyl cellulose (7H4XF), 10.0wt% sorbitol, 20.0wt% hydroxypropyl cellulose (EXF) and 0.5wt% red iron oxide are taken; each of the above ingredients is passed through a 40-mesh stainless steel sieve and then dry granulated; the granules are sieved through a 1.2mm stainless steel sieve and then mixed with 0.5wt% colloidal silicon dioxide and 0.5wt% magnesium stearate to obtain push layer particles.

[0676] (3) Preparation of three-layer core

[0677] The drug-layer granules, the isolation layer material, and the push layer granules were compressed into a three-layer tablet core using a 7.5 mm round punch. 758.6 mg of the drug-layer granules were added to the punch and compacted. Then, 50 mg of ethylcellulose N10, the isolation layer material, was added to the punch and compacted. Finally, 379.3 mg of the push layer granules were added to the punch and compressed using a tablet press to form a contact three-layer tablet core. The final three-layer tablet core contained approximately 440 mg of levodopa.

[0678] (4) Preparation of osmotic pump tablets

[0679] The three-layer tablet core is wrapped with a coating film. The coating film raw material composition comprises, by weight percentage, 50 wt% cellulose acetate, 5 wt% polyethylene glycol 400, and 45 wt% copovidone VA 64, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% acetyl groups. The coating film raw material composition is dissolved in acetone to form a solution with a solid content of 4%. The solution is sprayed onto the three-layer tablet core using a pan coating machine to form a coating film to obtain an osmotic pump tablet. Based on the resulting osmotic pump tablet, the coating film content is 4.5 wt%. A 1.0 mm drug release hole is drilled in the coating film using a laser or a machine.

[0680] The release profile of the final dosage form was measured in simulated saliva using the USPI paddle plate method. The osmotic pump tablet of this embodiment can be retained in the oral cavity, releasing 85% of the active drug from the tablet for approximately 5 hours. The released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentrations. The retention of the active drug ingredient at the release site is less than 10%.

[0681] Example 54 Preparation of Osmotic Pump Tablets

[0682] An osmotic pump tablet designed, formed, and suitable for use with Example 30, comprising levodopa and carbidopa monohydrate, is prepared as follows:

[0683] (1) A drug-containing layer was prepared, comprising two parts. Based on the total weight of the drug-containing layer, the first part contained 54.9 wt% of levodopa, 15.0 wt% of hydroxypropylcellulose with a weight-average molecular weight of 80,000, 5.0 wt% of povidone (K29 / 32), 3.07 wt% of sorbitol, and 0.9 wt% of aspartame, each of which was sieved through a 40-mesh stainless steel sieve, then wet-granulated, fluidized-bed dried, and granulated through a 1.2 mm stainless steel sieve. The second part contained 3.16 wt% of carbidopa monohydrate, 11.8 wt% of sorbitol, and 5.0 wt% of poloxamer (P407), each of which was sieved through a 40-mesh stainless steel sieve, then hot-melt granulated, and granulated through a 1.2 mm stainless steel sieve. The first part of the granules and the second part of the granules were mixed, and then 0.1 wt% of mint essence, 0.1 wt% of butylated hydroxytoluene and 1.0 wt% of magnesium stearate were added and mixed to obtain drug-layered granules.

[0684] (2) Preparation of boost layer

[0685] Based on the total weight of the push layer, 68.5wt% sodium carboxymethyl cellulose (7H4XF), 10.0wt% sorbitol, 20.0wt% hydroxypropyl cellulose (EXF) and 0.5wt% red iron oxide are taken; each is passed through a 40-mesh stainless steel sieve and then dry granulated; the granules are sieved through a 1.2mm stainless steel sieve and then mixed with 0.5wt% colloidal silicon dioxide and 0.5wt% magnesium stearate to obtain push layer particles.

[0686] (3) Preparation of double-layer tablet core

[0687] The drug-layer granules and the push-layer granules were compressed into bilayer cores using a 7.0 mm round punch. 563.9 mg of the drug-layer granules were added to the punch and compacted. Then, 282.0 mg of the push-layer granules were added to the punch. The two layers of granules were compressed into contacting bilayer tablets. The final bilayer tablets contained 309.4 mg of levodopa and 16.5 mg of carbidopa.

[0688] (4) Preparation of osmotic pump tablets

[0689] The bilayer tablet core is wrapped with a coating film. The raw material composition of the coating film comprises, by weight percentage, 50 wt% cellulose acetate having an acetyl content of 39.8 wt%, 5 wt% polyethylene glycol 400, and 45 wt% copovidone VA 64. The raw material composition is dissolved in acetone to form a 4% solution. The solution is sprayed onto the bilayer tablet core using a pan coating machine to form a coating film, thereby obtaining an osmotic pump tablet. Based on the resulting osmotic pump tablet, the coating film content is 7.0 wt%. A 1.0 mm drug release hole is drilled in the coating film using a laser or a machine.

[0690] (5) Preparation of outer coating

[0691] The outer coating composition includes 49.2 wt% levodopa, 28.3 wt% carbidopa, 20.0 wt% hydroxypropylcellulose, 1.47 wt% butylated hydroxytoluene, and 1.0% triethyl citrate. These components are prepared into a 10 wt% solution in ethanol and sprayed onto the osmotic pump tablets using a pan coater. The outer coating layer contains 18.75 mg levodopa and 10.8 mg carbidopa.

[0692] The bilayer osmotic pump tablet of this embodiment can be maintained in the oral cavity, releasing 85% of the active drug in the tablet for approximately 8 hours. The released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentrations. The retention of the active drug ingredient at the release site is less than 10%.

[0693] Example 55 Preparation of Osmotic Pump Tablets

[0694] An osmotic pump tablet designed, formed, and suitable for use with Example 30, containing the active pharmaceutical ingredients levodopa and carbidopa monohydrate, is prepared as follows:

[0695] (1) A drug-containing layer is prepared, which comprises two parts. Based on the total weight of the drug-containing layer, the first part comprises 54.9 wt% of levodopa, 15.0 wt% of hydroxypropylcellulose with a weight-average molecular weight of 80,000, 8.07 wt% of mannitol, and 0.9 wt% of aspartame. Each of the parts is sieved through a 40-mesh stainless steel sieve, then wet-granulated, fluidized-bed dried, and sieved through a 1.2 mm stainless steel sieve. The second part comprises 3.16 wt% of carbidopa monohydrate, 11.8 wt% of mannitol, and 5.0 wt% of poloxamer (P407). Each of the parts is sieved through a 40-mesh stainless steel sieve, then hot-melt granulated, and sieved through a 1.2 mm stainless steel sieve. The first and second part granules are mixed, and then 0.1 wt% of mint essence, 0.1 wt% of butylated hydroxytoluene, and 1.0 wt% of magnesium stearate are added to the mixture to obtain drug-containing layer granules.

[0696] (2) Preparation of boost layer

[0697] Based on the total weight of the push layer, 68.5wt% sodium carboxymethyl cellulose (7H4XF), 10.0wt% sorbitol, 20.0wt% hydroxypropyl cellulose (EXF) and 0.5wt% red iron oxide are taken; these ingredients are individually passed through a 40-mesh stainless steel screen and then dry granulated; after finishing through a 1.2mm stainless steel screen, they are mixed with 0.5wt% colloidal silicon dioxide and 0.5wt% magnesium stearate to obtain push layer particles.

[0698] (3) Preparation of double-layer tablet core

[0699] The drug-layer granules and the push-layer granules were compressed into bilayer cores using a 7.0 mm round punch. 563.9 mg of drug-layer granules were added to the punch and compacted. Then, 282.0 mg of osmotic-layer granules were added to the punch. The two layers were compressed into contacting bilayer cores using a tablet press. The final bilayer core contained 309.4 mg of levodopa and 16.5 mg of carbidopa.

[0700] (4) Preparation of osmotic pump tablets

[0701] The bilayer tablet core is coated with a film. The raw material composition of the film comprises, by weight percentage, 50% cellulose acetate with an acetyl content of 39.8% by weight, 5% polyethylene glycol 400, and 45% copovidone VA 64. This raw material composition is dissolved in acetone to form a 4% solution. The solution is sprayed onto the bilayer tablet using a pan coater to form a film coating. Based on the resulting osmotic pump tablet, the film coating has a 7.0% acetyl content. 1.0 mm drug release holes are drilled in the film using a laser or a machine.

[0702] (5) Preparation of outer coating

[0703] The outer coating composition includes 55.4 wt% levodopa, 31.9 wt% carbidopa, 10.0 wt% hydroxypropylcellulose (EXF), 1.66 wt% butylated hydroxytoluene, and 1.0 wt% triethyl citrate. These components are prepared into a 10 wt% solution in ethanol and sprayed onto the controlled-release tablets using a pan coater. The outer coating layer contains 18.75 mg levodopa and 10.8 mg carbidopa.

[0704] The bilayer osmotic pump tablet of this embodiment can be maintained in the oral cavity, releasing 85% of the active drug in the tablet for approximately 8 hours. The released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentrations. The retention of the active drug ingredient at the release site is less than 10%.

[0705] Example 56 Preparation of Osmotic Pump Tablets

[0706] An osmotic pump tablet designed, formed, and suitable for use with Example 30, containing the active pharmaceutical ingredients levodopa and carbidopa monohydrate, is prepared as follows:

[0707] (1) A drug-containing layer is prepared, which comprises two parts. Based on the total weight of the drug-containing layer, the first part comprises 54.9 wt% of levodopa, 15.0 wt% of hydroxypropylcellulose with a weight-average molecular weight of 80,000, 8.07 wt% of mannitol, and 0.9 wt% of aspartame. Each of the parts is sieved through a 40-mesh stainless steel sieve, then wet-granulated, fluidized-bed dried, and sieved through a 1.2 mm stainless steel sieve. The second part comprises 3.16 wt% of carbidopa monohydrate, 11.8 wt% of mannitol, and 5.0 wt% of poloxamer (P407). Each of the parts is sieved through a 40-mesh stainless steel sieve, then hot-melt granulated, and sieved through a 1.2 mm stainless steel sieve. The first and second part granules are mixed, and then 0.1 wt% of mint essence, 0.1 wt% of butylated hydroxytoluene, and 1.0 wt% of magnesium stearate are added to the mixture to obtain drug-containing layer granules.

[0708] (2) Preparation of boost layer

[0709] Based on the total weight of the push layer, 68.5wt% sodium carboxymethyl cellulose (7H4XF), 10.0wt% sorbitol, 20.0wt% hydroxypropyl cellulose (EXF) and 0.5wt% red iron oxide are taken; each is passed through a 40-mesh stainless steel sieve and then dry granulated; the granules are sieved through a 1.2mm stainless steel sieve and then mixed with 0.5wt% colloidal silicon dioxide and 0.5wt% magnesium stearate to obtain push layer particles.

[0710] (3) Preparation of double-layer tablet core

[0711] The drug-layer granules and the push-layer granules were compressed into bilayer cores using a 7.0 mm round punch. 563.9 mg of drug-layer granules were added to the punch and compacted. Then, 282.0 mg of osmotic-layer granules were added to the punch. The two layers were compressed into contacting bilayer cores using a tablet press. The final bilayer core contained 412.5 mg of levodopa and 23.8 mg of carbidopa.

[0712] (4) Preparation of osmotic pump tablets

[0713] The bilayer tablet core is coated with a film. The raw material composition of the film comprises, by weight, 50% cellulose acetate with an acetyl content of 39.8% by weight, 5% polyethylene glycol 400, and 45% copovidone VA 64. This composition is dissolved in acetone to form a 4% solution, which is then sprayed onto the bilayer tablet using a pan coater to form a film coating. Based on the resulting osmotic pump tablet, the film coating comprises 5.5% by weight. 1.0 mm drug release holes are drilled in the film using a laser or a machine.

[0714] The bilayer osmotic pump tablet of this embodiment can be maintained in the oral cavity, releasing 85% of the active drug in the tablet for approximately 8 hours. The released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing sustained and stable drug absorption and blood drug concentrations. The retention of the active drug ingredient at the release site is less than 10%.

[0715] Example 57 Capsule-shaped tablet specifications 25 mg / 100 mg (carbidopa / levodopa)

[0716] The prescription is as shown in Table 5:

[0717] Table 5

[0718] Preparation method:

[0719] (1) Preparation of drug-containing layer

[0720] Based on the total weight of the drug-containing layer, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone (K29 / 32), and 18.0 wt% of mannitol were taken and then dry granulated; the granules were sieved through a 16-mesh stainless steel mesh and then mixed with 1.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0721] (2) Preparation of boost layer

[0722] Based on the total weight of the push layer, 55.0 wt% of sodium carboxymethyl cellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose (EXF) and 0.50 wt% of red iron oxide are taken and then dry granulated; the granules are sieved through a 16-mesh stainless steel mesh and then mixed with 0.50 wt% of magnesium stearate to obtain push layer granules.

[0723] (3) Preparation of double-layer tablet core

[0724] The drug-containing layer granules and the booster layer granules are pressed into a double-layer tablet core. The die size is (shallow concave). The drug-containing layer granules obtained in step (1) (about 166.69 mg) were added to the punch of the tablet press and compacted. Then, the booster layer granules obtained in step (2) (about 83.27 mg) were added to the punch, and the two layers of granules were compressed into contact double-layer tablet cores (about 249.96 mg) using a tablet press.

[0725] (4) Preparation of osmotic pump tablets

[0726] The bilayer tablet cores are coated with a film. The raw material composition of the film comprises, by weight, 65.0 wt% cellulose acetate and 35.0 wt% copovidone VA 64, wherein the cellulose acetate contains 39.8 wt% acetyl groups. This composition is dissolved in acetone / anhydrous ethanol (V:V = 9:1) to a solids content of 4.0%. This solution is sprayed onto the bilayer tablet cores using a pan coater to form a coating film, which accounts for approximately 10.0% of the weight of the bilayer tablet cores. The film is then further coated with a drug-containing immediate-release overcoat. The raw material composition of the drug-containing immediate-release overcoat comprises, by weight, 46.7 wt% carbidopa monohydrate, 43.3 wt% levodopa, and 10.0 wt% hydroxypropylcellulose (EXF). This composition is dissolved in anhydrous ethanol to a solids content of 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, yielding an osmotic pump tablet. The perforations are mechanically or laser-drilled, with a drug-release aperture diameter of 1.0 mm. The osmotic pump tablets in this example are 25 mg / 100 mg (carbidopa / levodopa) and are round, biconvex tablets.

[0727] Take this product and test it according to the dissolution and release method (General Rules of Chinese Pharmacopoeia) <0931> First Law and USP <711> Method 1: Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium at 75 rpm. Follow the procedure described. Samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours.

[0728] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 6 hours (as shown in Figure 39), and the active ingredient carbidopa in the drug-containing rapid-release outer coating is 104% released at 0.5 h, with an SD value of 10.5%.

[0729] Example 58 Capsule-shaped tablet specifications 25 mg / 100 mg (carbidopa / levodopa)

[0730] The prescription is as shown in Table 6:

[0731] Table 6

[0732] Preparation method:

[0733] (1) Preparation of drug-containing layer

[0734] Based on the total weight of the drug-containing layer, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone (K29 / 32), 16.5 wt% of mannitol, and 0.50 wt% of colloidal silicon dioxide were taken and then dry granulated; the granules were sieved through a 16-mesh stainless steel mesh and then mixed with 2.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0735] (2) Preparation of boost layer

[0736] Based on the total weight of the push layer, 49.0 wt% of sodium carboxymethyl cellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF) and 0.5 wt% of red iron oxide are taken and then dry granulated; the granules are sieved through a 16-mesh stainless steel mesh and then mixed with 0.5 wt% of magnesium stearate to obtain push layer granules.

[0737] (3) Preparation of double-layer tablet core

[0738] The drug-containing layer granules and the booster layer granules are pressed into a double-layer tablet core. The die size is (shallow concave). The drug-containing layer granules obtained in step (1) (about 166.69 mg) were added to the punch of the tablet press and compacted. Then, the booster layer granules obtained in step (2) (about 83.34 mg) were added to the punch, and the two layers of granules were compressed into contact double-layer tablet cores (about 250.03 mg) using a tablet press.

[0739] (4) Preparation of osmotic pump tablets

[0740] The bilayer tablet cores are coated with a film. The raw material composition of the film comprises, by weight, 65.0 wt% cellulose acetate and 35.0 wt% copovidone VA 64, wherein the cellulose acetate contains 39.8 wt% acetyl groups. This composition is dissolved in acetone / anhydrous ethanol (V:V = 9:1) to a solids content of 4.0%. This solution is sprayed onto the bilayer tablet cores using a pan coater to form a coating film, which accounts for approximately 10.0% of the weight of the bilayer tablet cores. The film is then further coated with a drug-containing immediate-release overcoat. The raw material composition of the drug-containing immediate-release overcoat comprises, by weight, 46.7 wt% carbidopa monohydrate, 43.3 wt% levodopa, and 10.0 wt% hydroxypropylcellulose (EXF). This composition is dissolved in anhydrous ethanol to a solids content of 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, yielding osmotic pump tablets. The perforations are mechanically or laser-drilled, with a drug-release aperture diameter of 1.0 mm. The controlled-release tablets in this example are 25 mg / 100 mg (carbidopa / levodopa) and are round, biconvex tablets.

[0741] Take this product and test it according to the dissolution and release method (General Rules of Chinese Pharmacopoeia) <0931> First Law and USP <711> Method 1: Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium at 75 rpm. Follow the procedure described. Samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours.

[0742] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 6 hours (as shown in Figure 40), and the active ingredient carbidopa in the drug-containing rapid-release outer coating is 104% released in 0.5 hours, with an SD value of 10.5%.

[0743] Example 59 Capsule-shaped tablet specifications 25 mg / 150 mg (carbidopa / levodopa)

[0744] The prescription is as shown in Table 7:

[0745] Table 7

[0746] Preparation method:

[0747] (1) Preparation of drug-containing layer

[0748] Based on the total weight of the drug-containing layer, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone (K29 / 32), and 18.0 wt% of mannitol were taken and then dry granulated; the granules were sieved through a 16-mesh stainless steel mesh and then mixed with 1.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0749] (2) Preparation of boost layer

[0750] Based on the total weight of the push layer, 55.0 wt% of sodium carboxymethyl cellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose (EXF) and 0.50 wt% of red iron oxide are taken and then dry granulated; the granules are sieved through a 16-mesh stainless steel mesh and then mixed with 0.50 wt% of magnesium stearate to obtain push layer granules.

[0751] (3) Preparation of double-layer tablet core

[0752] The drug-containing layer granules and the booster layer granules are pressed into a double-layer tablet core. The die size is (shallow concave). The drug-containing layer granules obtained in step (1) (about 250 mg) were added to the punch of the tablet press and compacted. Then, the booster layer granules obtained in step (2) (about 125.06 mg) were added to the punch, and the two layers of granules were compressed into contact double-layer tablet cores (about 375.06 mg) using a tablet press.

[0753] (4) Preparation of osmotic pump tablets

[0754] The bilayer tablet core is coated with a film. The raw material composition of the film comprises, by weight, 65.0 wt% cellulose acetate and 35.0 wt% copovidone VA 64, wherein the cellulose acetate contains 39.8 wt% acetyl groups. This composition is dissolved in acetone / anhydrous ethanol (V:V = 9:1) to a solids content of 4.0%. The solution is sprayed onto the bilayer tablet core using a pan coater to form a coating film, which accounts for approximately 8.0% of the weight of the bilayer tablet core. The film is then further coated with a drug-containing immediate-release overcoat. The raw material composition of the drug-containing immediate-release overcoat comprises, by weight, 37.7 wt% carbidopa monohydrate, 52.3 wt% levodopa, and 10.0 wt% hydroxypropylcellulose (EXF). This composition is dissolved in anhydrous ethanol to a solids content of 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, yielding osmotic pump tablets. The perforations are mechanically or laser-drilled, with a drug-release aperture diameter of 1.0 mm. The controlled-release tablets in this example are 25 mg / 150 mg (carbidopa / levodopa), round, biconvex tablets.

[0755] Take this product and test it according to the dissolution and release method (General Rules of Chinese Pharmacopoeia) <0931> First Law and USP <711> Method 1: Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium at 75 rpm. Follow the procedure described. Samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours.

[0756] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 6 hours (as shown in Figure 41), and the active ingredient carbidopa in the drug-containing rapid-release outer coating is 96% released in 0.5 hours, with an SD value of 12%.

[0757] Example 60 Capsule-shaped tablet specifications 25 mg / 150 mg (carbidopa / levodopa)

[0758] The prescription is as shown in Table 8:

[0759] Table 8

[0760] Preparation method:

[0761] (1) Preparation of drug-containing layer

[0762] Based on the total weight of the drug-containing layer, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone (K29 / 32), 16.5 wt% of mannitol, and 0.50 wt% of colloidal silicon dioxide were taken and then dry granulated; the granules were sieved through a 16-mesh stainless steel mesh and then mixed with 2.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0763] (2) Preparation of boost layer

[0764] Based on the total weight of the push layer, 49.0 wt% of sodium carboxymethyl cellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF) and 0.50 wt% of red iron oxide are taken and then dry granulated; the granules are sieved through a 16-mesh stainless steel mesh and then mixed with 0.50 wt% of magnesium stearate to obtain push layer granules.

[0765] (3) Preparation of double-layer tablet core

[0766] The drug-containing layer granules and the booster layer granules are pressed into a double-layer tablet core. The die size is (shallow concave). The drug-containing layer granules obtained in step (1) (about 250.05 mg) were added to the punch of the tablet press and compacted. Then, the booster layer granules obtained in step (2) (about 125.06 mg) were added to the punch, and the two layers of granules were compressed into contact double-layer tablet cores (about 375.11 mg) using a tablet press.

[0767] (4) Preparation of osmotic pump tablets

[0768] The bilayer tablet core is coated with a film. The raw material composition of the film comprises, by weight, 65.0 wt% cellulose acetate and 35.0 wt% copovidone VA 64, wherein the cellulose acetate contains 39.8 wt% acetyl groups. The film is dissolved in acetone / anhydrous ethanol (V:V = 9:1) to a solids content of 4.0%. The solution is sprayed onto the bilayer tablet core using a pan coater to form a coating film, which accounts for 8.0% of the weight of the bilayer tablet core. The film is then further coated with a drug-containing immediate-release overcoat. The raw material composition of the drug-containing immediate-release overcoat comprises, by weight, 37.7 wt% carbidopa monohydrate, 52.3 wt% levodopa, and 10.0 wt% hydroxypropylcellulose (EXF). The film is dissolved in anhydrous ethanol to a solids content of 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, yielding osmotic pump tablets. The perforations are mechanically or laser-drilled, with a drug-release aperture diameter of 1.0 mm. The controlled-release tablets in this example are 25 mg / 150 mg (carbidopa / levodopa), round, biconvex tablets.

[0769] Take this product and test it according to the dissolution and release method (General Rules of Chinese Pharmacopoeia) <0931> First Law and USP <711> Method 1: Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium at 75 rpm. Follow the procedure described. Samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours.

[0770] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 6 hours (as shown in Figure 42), and the active ingredient carbidopa in the drug-containing rapid-release outer coating is 96% released at 0.5 h, with an SD value of 12%.

[0771] Example 61 Capsule-shaped tablet specifications 25 mg / 250 mg (carbidopa / levodopa)

[0772] The prescription is as shown in Table 9:

[0773] Table 9

[0774] Preparation method:

[0775] (1) Preparation of drug-containing layer

[0776] Based on the total weight of the drug-containing layer, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone (K29 / 32), and 18.0 wt% of mannitol were taken and then dry granulated; the granules were sieved through a 16-mesh stainless steel mesh and then mixed with 1.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0777] (2) Preparation of boost layer

[0778] Based on the total weight of the push layer, 55.0 wt% of sodium carboxymethyl cellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose (EXF) and 0.50 wt% of red iron oxide are taken and then dry granulated; the granules are sieved through a 16-mesh stainless steel mesh and then mixed with 0.50 wt% of magnesium stearate to obtain push layer granules.

[0779] (3) Preparation of double-layer tablet core

[0780] The drug-containing layer granules and the booster layer granules are pressed into a double-layer tablet core. The die size is (shallow concave). The drug-containing layer granules obtained in step (1) (about 416.66 mg) were added to the punch of the tablet press and compacted. Then, the booster layer granules obtained in step (2) (about 208.28 mg) were added to the punch, and the two layers of granules were compressed into contact double-layer tablet cores (about 624.94 mg) using a tablet press.

[0781] (4) Preparation of osmotic pump tablets

[0782] The bilayer tablet core is coated with a film. The raw material composition of the film comprises, by weight, 65.0 wt% cellulose acetate and 35.0 wt% copovidone VA 64, wherein the cellulose acetate contains 39.8 wt% acetyl groups. The film is dissolved in acetone / anhydrous ethanol (V:V = 9:1) to a solids content of 4.0%. The solution is sprayed onto the bilayer tablet core using a pan coater to form a coating film, which accounts for 6.5% of the weight of the bilayer tablet core. The film is then further coated with a drug-containing immediate-release overcoat. The raw material composition of the drug-containing immediate-release overcoat comprises, by weight, 27.2 wt% carbidopa monohydrate, 62.9 wt% levodopa, and 10.0 wt% hydroxypropylcellulose (EXF). The film is dissolved in anhydrous ethanol to a solids content of 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, yielding osmotic pump tablets. The perforations are mechanically or laser-drilled, with a drug-release aperture diameter of 1.0 mm. The controlled-release tablets in this example are 25 mg / 250 mg (carbidopa / levodopa), round, biconvex tablets.

[0783] Take this product and test it according to the dissolution and release method (General Rules of Chinese Pharmacopoeia) <0931> First Law and USP <711> Method 1: Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium at 75 rpm. Follow the procedure described. Samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours.

[0784] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 6 hours (as shown in Figure 43), and the active ingredient carbidopa in the drug-containing rapid-release outer coating is 93% released in 0.5 hours, with an SD value of 4.6%.

[0785] Example 62 Capsule-shaped tablet specifications 25 mg / 250 mg (carbidopa / levodopa)

[0786] The prescription is as shown in Table 10:

[0787] Table 10

[0788] Preparation method:

[0789] (1) Preparation of drug-containing layer

[0790] Based on the total weight of the drug-containing layer, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone (K29 / 32), 16.5 wt% of mannitol, and 0.50 wt% of colloidal silicon dioxide were taken and then dry granulated; the granules were sieved through a 16-mesh stainless steel mesh and then mixed with 2.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0791] (2) Preparation of boost layer

[0792] Based on the total weight of the push layer, 49.0 wt% of sodium carboxymethyl cellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF) and 0.5 wt% of red iron oxide are taken and then dry granulated; the granules are sieved through a 16-mesh stainless steel mesh and then mixed with 0.5 wt% of magnesium stearate to obtain push layer granules.

[0793] (3) Preparation of double-layer tablet core

[0794] The drug-containing layer granules and the booster layer granules are pressed into a double-layer tablet core. The die size is (shallow concave). The drug-containing layer granules obtained in step (1) (about 416.71 mg) were added to the punch of the tablet press and compacted. Then, the booster layer granules obtained in step (2) (about 208.28 mg) were added to the punch, and the two layers of granules were compressed into contact double-layer tablet cores (about 624.99 mg) using a tablet press.

[0795] (4) Preparation of osmotic pump tablets

[0796] The bilayer tablet core is coated with a film. The raw material composition of the film comprises, by weight, 65.0 wt% cellulose acetate and 35.0 wt% copovidone VA 64, wherein the cellulose acetate contains 39.8 wt% acetyl groups. This composition is dissolved in acetone / anhydrous ethanol (V:V = 9:1) to a solids content of 4.0%. The solution is sprayed onto the bilayer tablet core using a pan coater to form a coating film, which accounts for approximately 6.5% of the weight of the bilayer tablet core. The film is then further coated with a drug-containing immediate-release overcoat. The raw material composition of the drug-containing immediate-release overcoat comprises, by weight, 37.7 wt% carbidopa monohydrate, 52.3 wt% levodopa, and 10.0 wt% hydroxypropylcellulose (EXF). This composition is dissolved in anhydrous ethanol to a solids content of 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, yielding osmotic pump tablets. The perforations are mechanically or laser-drilled, with a drug-release aperture diameter of 1.0 mm. The controlled-release tablets in this example are 25 mg / 250 mg (carbidopa / levodopa), round, biconvex tablets.

[0797] Take this product and test it according to the dissolution and release method (General Rules of Chinese Pharmacopoeia) <0931> First Law and USP <711> Method 1: Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium at 75 rpm. Follow the procedure described. Samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 hours.

[0798] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 6 hours (as shown in Figure 44), and the active ingredient carbidopa in the drug-containing rapid-release outer coating is 93% released in 0.5 hours, with an SD value of 4.6%.

[0799] Example 63 Capsule-shaped tablet specifications 62.5 mg / 250 mg (carbidopa / levodopa)

[0800] The prescription is as shown in Table 11:

[0801] Table 11

[0802] Preparation method:

[0803] (1) Preparation of drug-containing layer

[0804] Based on the total weight of the drug-containing layer, 63.0 wt% of levodopa, 11.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone (K29 / 32), 10.0 wt% of sorbitol, and 10.0 wt% of poloxamer (P407) were taken and then dry granulated; the granules were sieved through a 16-mesh stainless steel mesh and then mixed with 1.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0805] (2) Preparation of boost layer

[0806] Based on the total weight of the push layer, 49.0 wt% of sodium carboxymethyl cellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF) and 0.50 wt% of red iron oxide are taken and then dry granulated; the granules are sieved through a 16-mesh stainless steel mesh and then mixed with 0.50 wt% of magnesium stearate to obtain push layer granules.

[0807] (3) Preparation of double-layer tablet core

[0808] The drug-containing layer granules and the booster layer granules are pressed into a double-layer tablet core. The die size is (shallow concave). The drug-containing layer granules obtained in step (1) (about 396.76 mg) were added to the punch of the tablet press and compacted. Then, the booster layer granules obtained in step (2) (about 198.38 mg) were added to the punch, and the two layers of granules were compressed into contact double-layer tablet cores (about 595.14 mg) using a tablet press.

[0809] (4) Preparation of osmotic pump tablets

[0810] The bilayer tablet core is coated with a coating film. The raw material composition of the coating film comprises, by weight, 65.0 wt% cellulose acetate and 35.0 wt% copovidone VA 64, wherein the cellulose acetate contains 39.8 wt% acetyl groups. This composition is dissolved in acetone / anhydrous ethanol (V:V = 9:1) to a solids content of 4.0%. This solution is sprayed onto the bilayer tablet core using a pan coater to form a coating film, which accounts for approximately 9.5% of the weight of the bilayer tablet core. The coating film is then further coated with a drug-containing immediate-release overcoat. The raw material composition of the drug-containing immediate-release overcoat comprises, by weight, 90.0 wt% carbidopa monohydrate and 10.0 wt% hydroxypropylcellulose (EXF). This composition is dissolved in anhydrous ethanol to a solids content of 10.0%. This solution is sprayed onto the coating film using a pan coater to form the drug-containing immediate-release overcoat, thereby producing an osmotic pump tablet. The holes are punched mechanically or by laser, and the diameter of the drug release holes is 1.0 mm. The specifications of the controlled-release tablets in this embodiment are 62.5 mg / 250 mg (carbidopa / levodopa), and they are round biconvex tablets.

[0811] Take this product and test it according to the dissolution and release method (General Rules of Chinese Pharmacopoeia) <0931> First Law and USP <711> Method 1: Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium at 75 rpm. Sampling was performed according to the procedure at 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 10 hours.

[0812] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 10 hours (as shown in Figure 45), and the active ingredient carbidopa in the drug-containing rapid-release outer coating is 98% released in 0.5 hours, with an SD value of 6.4%.

[0813] Example 64 Capsule-shaped tablet specifications 62.5 mg / 250 mg (carbidopa / levodopa)

[0814] The prescription is as shown in Table 12:

[0815] Table 12

[0816] Preparation method:

[0817] (1) Preparation of drug-containing layer

[0818] Based on the total weight of the drug-containing layer, 63.0 wt% of levodopa, 11.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of povidone (K29 / 32), 8.50 wt% of sorbitol, 10.0 wt% of poloxamer (P407), and 0.50 wt% of colloidal silicon dioxide were taken and then dry granulated. The granules were passed through a 16-mesh stainless steel sieve and then mixed with 2.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0819] (2) Preparation of boost layer

[0820] Based on the total weight of the push layer, 49.0 wt% of sodium carboxymethyl cellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF) and 0.50 wt% of red iron oxide are taken and then dry granulated; the granules are sieved through a 16-mesh stainless steel mesh and then mixed with 0.50 wt% of magnesium stearate to obtain push layer granules.

[0821] (3) Preparation of double-layer tablet core

[0822] The drug-containing layer granules and the booster layer granules are pressed into a double-layer tablet core. The die size is (shallow concave). The drug-containing layer granules obtained in step (1) (about 396.72 mg) were added to the punch of the tablet press and compacted. Then, the booster layer granules obtained in step (2) (about 198.38 mg) were added to the punch, and the two layers of granules were compressed into contact double-layer tablet cores (about 595.1 mg) using a tablet press.

[0823] (4) Preparation of osmotic pump tablets

[0824] The bilayer tablet core is coated with a coating film. The raw material composition of the coating film comprises, by weight, 65.0 wt% cellulose acetate and 35.0 wt% copovidone VA 64, wherein the cellulose acetate contains 39.8 wt% acetyl groups. This composition is dissolved in acetone / anhydrous ethanol (V:V = 9:1) to a solids content of 4.0%. This solution is sprayed onto the bilayer tablet core using a pan coater to form a coating film, which accounts for approximately 9.5% of the weight of the bilayer tablet core. The coating film is then further coated with a drug-containing immediate-release overcoat. The raw material composition of the drug-containing immediate-release overcoat comprises, by weight, 90.0 wt% carbidopa monohydrate and 10.0 wt% hydroxypropylcellulose (EXF). This composition is dissolved in anhydrous ethanol to a solids content of 10.0%. This solution is sprayed onto the coating film using a pan coater to form the drug-containing immediate-release overcoat, thereby producing an osmotic pump tablet. The holes are punched mechanically or by laser, and the diameter of the drug release holes is 1.0 mm. The specifications of the controlled-release tablets in this embodiment are 62.5 mg / 250 mg (carbidopa / levodopa), and they are round biconvex tablets.

[0825] Take this product and test it according to the dissolution and release method (General Rules of Chinese Pharmacopoeia) <0931> First Law and USP <711> Method 1: Use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium at 75 rpm. Sampling was performed according to the procedure at 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 10 hours.

[0826] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 10 hours (as shown in Figure 46), and the active ingredient carbidopa in the drug-containing rapid-release outer coating is 98% released in 0.5 hours, with an SD value of 6.4%.

[0827] Comparative Example A

[0828] Preparation of osmotic pump tablets (immersion experiment)

[0829] The procedure of Example 47 was repeated in this comparative example, except that:

[0830] (1) The drug-containing layer contains 63.0 wt% of levodopa, 5.0 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 10.0 wt% of povidone (K29 / 32), 15.0 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint flavor and 1.0 wt% of magnesium stearate.

[0831] The release profile of the final dosage form was measured in simulated saliva using the USPI paddle plate method. Figure 48 depicts the release profile of the LD. The release of the active drug failed to reach 85%. Observations revealed rupture of the controlled release membrane during dissolution, as shown in Figure 47.

[0832] Comparative Example B

[0833] Preparation of osmotic pump tablets (high dissolution residue)

[0834] In this example, the procedure of Example 47 was repeated, except that the drug-containing layer contained 63.0 wt % of levodopa, 5.0 wt % of hydroxypropyl cellulose having a weight-average molecular weight of 80,000, 10.0 wt % of povidone (K29 / 32), 15.0 wt % of mannitol, 0.9 wt % of aspartame, 0.1 wt % of mint flavor, and 1.0 wt % of magnesium stearate.

[0835] The release profile of the final manufactured dosage form was planned to be measured in simulated saliva using the USPI paddle plate method. Figure 49 depicts the release profile of the LD. The release of the active drug did not reach 85%, the residual amount of active drug was large, and only 67.5% of the active drug was released after 4 hours of release into the plateau.

Claims

1. An osmotic pump tablet, characterized in that, It is any of the following solutions: Solution (1): The osmotic pump tablet comprises a tablet core and a coating film wrapping the tablet core. The coating film is provided with drug release holes. The tablet core includes a drug-containing layer, and the drug-containing layer contains a drug active ingredient, a hydrophilic polymer, and a surfactant. The hydrophilic polymer includes hydroxypropyl cellulose, and the surfactant includes poloxamer; Solution (2): The osmotic pump tablet comprises a tablet core, a coating film wrapping the tablet core, and a drug-containing rapid-release outer coating. The coating film is provided with drug release holes. The tablet core includes a drug-containing layer, and the drug-containing layer contains a drug active ingredient and a hydrophilic polymer, but does not contain a surfactant; the hydrophilic polymer includes povidone K29 / 32; Or Solution (3): The osmotic pump tablet comprises a tablet core, a coating film wrapping the tablet core, and a drug-containing rapid-release outer coating. The coating film is provided with drug release holes. The tablet core includes a drug-containing layer, and the drug-containing layer contains a drug active ingredient and excipients; the drug-containing rapid-release outer coating contains a drug active ingredient and pharmaceutical excipients, and the pharmaceutical excipient is a binder.

2. The osmotic pump tablet according to claim 1, wherein Solution (1) satisfies one or more of the following conditions (a) to (k): (a) Based on the total weight of the drug-containing layer, the content of the hydrophilic polymer is 5 wt% - 25 wt%, for example 10 wt% - 20 wt%, and for example 10 wt% - 15 wt%; (b) The hydroxypropyl cellulose is hydroxypropyl cellulose EXF; (c) The hydrophilic polymer is a mixture of hydroxypropyl cellulose and one or more selected from hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone, and hydroxyethyl cellulose; (d) Based on the total weight of the drug-containing layer, the content of the surfactant is 1 wt% - 15 wt%, for example 2 wt% - 10 wt%, and for example 5 wt% - 10 wt%; (e) The poloxamer is poloxamer 407; (f) The surfactant is a mixture of poloxamer and one or more selected from polysorbate, fatty acid glyceride, sodium dodecylbenzenesulfonate, and sodium dodecyl sulfate; (g) Based on the total weight of the drug-containing layer, the content of the drug active ingredient is 50 wt% - 75 wt%, for example 55 wt% - 65 wt%, and for example 58 wt% - 63 wt%; (h) The drug active ingredient is a drug active ingredient for oral drug release, or a drug for oral local treatment or absorption at the upper digestive tract; (i) The drug active ingredient is selected from one or more of levodopa or its ester or its salt, carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin; preferably selected from one or two of levodopa or its ester and carbidopa; (j) The drug active ingredient is selected from antifungal drugs and anti-tumor drugs; wherein, the antifungal drug is, for example, selected from one or more of nystatin, fluconazole, posaconazole, isavuconazole, voriconazole, anidulafungin, caspofungin, and micafungin; (k) The drug-containing layer further comprises other excipients selected from one or more of a penetrant, a drug carrier, a binder, a lubricant, an antioxidant and a flavoring agent; Preferably, the penetrant is selected from one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose, lactose, starch, pregelatinized starch, dextrin and microcrystalline cellulose, such as sorbitol or mannitol; Preferably, based on the total weight of the drug-containing layer, the content of the penetrant is 0-50 wt%, but not 0, such as 5-20 wt%; Preferably, the drug carrier is selected from one or more of povidone (such as povidone K30 or povidone K29 / 32), copovidone, carbomer, hypromellose, hydroxyethyl cellulose, polyethylene oxide and sodium alginate; Preferably, based on the total weight of the drug-containing layer, the content of the drug carrier is 0-50 wt% but not 0%; such as 0.5-50 wt%, and again such as 5-50 wt%, for example 5-10 wt%; Preferably, the binder is selected from one or more of methylcellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, copovidone and gelatin; Preferably, based on the total weight of the drug-containing layer, the content of the binder is 5-50 wt%, such as 5.0 wt%; Preferably, the lubricant is one or more of stearic acid, magnesium stearate, magnesium stearyl fumarate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, talc and colloidal silica, such as one or two of magnesium stearate and colloidal silica; Preferably, based on the total weight of the drug-containing layer, the content of the lubricant is 0-3 wt%, but not 0, such as 0.5-2.5 wt%, and again such as 1 wt%-2 wt%; Preferably, the antioxidant can be one or more of dibutylhydroxytoluene, butylhydroxyanisole, tert-butylhydroquinone, propyl gallate, vitamin C and vitamin E, such as dibutylhydroxytoluene; Preferably, based on the total weight of the drug-containing layer, the content of the antioxidant is 0-1 wt%, but not 0; such as 0.01-0.1 wt%; Preferably, the flavoring agent is one or more of aspartame, apple essence, orange essence, banana essence, mint essence, sodium saccharin and stevioside, such as one or two of aspartame and mint essence; Preferably, based on the total weight of the drug-containing layer, the content of the flavoring agent is 0-10 wt%, or 0-2 wt, but not 0; such as 1.0 wt%; when the flavoring agent is a combination of aspartame and mint essence, the content of aspartame is 0.9 wt% and the content of mint essence is 0.1 wt%; Scheme (2) satisfies one or more of the following conditions (i) to (vii): (i) Based on the total weight of the drug-containing layer, the content of the drug active ingredient is 30-75 wt%, such as 38 wt%-65 wt%; (ii) (h) in Scheme (1); (iii) (i) in Scheme (1); (iv) (j) in Scheme (1); (v) Based on the total weight of the drug-containing layer, the content of the hydrophilic polymer povidone K29 / 32 is 0.5 - 50 wt%, for example 0.5 - 20 wt%, or 5 - 10 wt%; (vi) The hydrophilic polymer is a mixture of povidone K29 / 32 and one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and hydroxyethyl cellulose; (vii) The excipients are selected from one or more of fillers, osmotic agents, sour agents, lubricants, and flavoring agents; Preferably, when the excipients contain fillers, the fillers are one or more of microcrystalline cellulose, hydroxypropyl cellulose, and mannitol; based on the total weight of the drug-containing layer, the content of the fillers is preferably 0 - 50 wt% but not 0%; preferably 20 - 50 wt%, or 31 wt%; Preferably, when the excipients contain osmotic agents, the osmotic agents are one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, and glucose; based on the total weight of the drug-containing layer, the content of the osmotic agents is preferably 0 - 50 wt% but not 0%; for example 4 - 50 wt%; Preferably, when the excipients contain sour agents, the sour agents are one or more of citric acid, sodium citrate, potassium citrate, malic acid, fumaric acid, lactic acid, phosphoric acid, and tartaric acid; based on the total weight of the drug-containing layer, the content of the sour agents is preferably 0 - 10 wt% but not 0%; for example 5 wt% - 10 wt%; Preferably, when the excipients contain lubricants, the lubricants are one or more of magnesium stearate, magnesium stearyl fumarate, talc, and colloidal silica; for example one or two of magnesium stearate and colloidal silica; based on the total weight of the drug-containing layer, the content of the lubricants is 0.5 - 3 wt%; for example 0.5 - 2.5 wt%, or 1 - 2 wt%; Preferably, when the excipients contain flavoring agents, the flavoring agents are one or more of aspartame, apple essence, orange essence, banana essence, mint essence, sodium saccharin, and stevioside, for example one or two of aspartame and mint essence (when two are selected, they can exist in any proportion); preferably, based on the total weight of the drug-containing layer, the content of the flavoring agents is 0 - 10 wt%, but not 0; for example 1 - 6 wt%; or 2 - 5 wt%; Scheme (3) satisfies one or more of the following conditions ① to ⑩: ① In the drug-containing immediate-release outer coating, the pharmaceutical excipient is hydroxypropyl cellulose (EXF); ② In the drug-containing immediate-release outer coating, the content of the drug active ingredient is 80 - 90 wt%; the content of the binder is 10 - 20.0 wt%; ③ In the drug-containing immediate-release outer coating, the drug active ingredient contains levodopa and / or carbidopa, wherein when two drug active ingredients are contained, the mass ratio of levodopa to carbidopa is preferably 1:1 - 4:1; ④In the medicated layer, based on the total weight of the medicated layer, the content of the pharmaceutically active ingredient is 30-75 wt%, such as 38 wt%-65 wt%. ⑤In the medicated layer, the pharmaceutically active ingredient is (h) in Scheme (1). ⑥In the medicated layer, the pharmaceutically active ingredient is selected from (i) in Scheme (1). ⑦In the medicated layer, the pharmaceutically active ingredient is selected from (j) in Scheme (1). ⑧In the medicated layer, the excipients are selected from one or more of fillers, penetrants, sour agents, lubricants, flavoring agents, antioxidants, hydrophilic polymers, drug carriers, binders and surfactants. Preferably, when the excipients contain fillers, the filler is one or more of microcrystalline cellulose, hydroxypropyl cellulose and mannitol; based on the total weight of the medicated layer, the content of the filler is preferably 0-50 wt% but not 0%; preferably 20-50 wt%, such as 31 wt%. Preferably, when the excipients contain penetrants, the penetrant is one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose and glucose; based on the total weight of the medicated layer, the content of the penetrant is preferably 0-50 wt% but not 0%; such as 4-50 wt%. Preferably, when the excipients contain sour agents, the sour agent is one or more of citric acid, sodium citrate, potassium citrate, malic acid, fumaric acid, lactic acid, phosphoric acid and tartaric acid; based on the total weight of the medicated layer, the content of the sour agent is preferably 0-10 wt% but not 0%; such as 5 wt%-10 wt%. Preferably, when the excipients contain lubricants, the lubricant is one or more of magnesium stearate, magnesium stearate fumarate, talc powder and colloidal silica; such as one or two of magnesium stearate and colloidal silica; based on the total weight of the medicated layer, the content of the lubricant is 0.5-3 wt%; such as 0.5-2.5 wt%, and such as 1-2 wt%. Preferably, when the excipients contain flavoring agents, the flavoring agent is one or more of aspartame, apple essence, orange essence, banana essence, mint essence, sodium saccharin and stevioside, such as one or two of aspartame and mint essence (when two are selected, they can exist in any proportion); preferably, based on the total weight of the medicated layer, the content of the flavoring agent is 0-10 wt%, but not 0; such as 1-6 wt%; and such as 2-5 wt%. Preferably, when the excipients contain hydrophilic polymers, the hydrophilic polymer is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone and hydroxyethyl cellulose; preferably, based on the total weight of the medicated layer, the content of the hydrophilic polymer is 5 wt%-25 wt%, such as 10 wt%-20 wt%, and such as 10 wt%-15 wt%. Preferably, when the auxiliary material contains a drug carrier, the drug carrier is selected from one or more of povidone (such as povidone K30 or povidone K29 / 32), copovidone, carbomer, hypromellose, hydroxyethyl cellulose, polyethylene oxide, and sodium alginate; preferably, based on the total weight of the drug-containing layer, the content of the drug carrier is 0 - 50 wt% but not 0%; for example, 0.5 - 50 wt%, or 5 - 50 wt%, or 5 - 10 wt%; Preferably, when the auxiliary material contains a binder, the binder is selected from one or more of methyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone (such as povidone K30 or povidone K29 / 32), copovidone, and gelatin; preferably, based on the total weight of the drug-containing layer, the content of the binder is 0 - 50 wt% but not 0%; for example, 0.5 - 50 wt%, or 5 - 50 wt%, or 5 - 10 wt%; Preferably, when the auxiliary material contains a surfactant, the surfactant is selected from one or more of poloxamer, polysorbate, glycerol fatty acid ester, sodium dodecylbenzenesulfonate, and sodium dodecyl sulfate; preferably, based on the total weight of the drug-containing layer, the content of the surfactant is 1 wt% - 15 wt%, for example, 2 wt% - 10 wt%, or 5 wt% - 10 wt%.

3. The osmotic pump tablet according to claim 2, wherein The drug-containing layer is any one of the following combinations: (a) Drug active ingredient, hydrophilic polymer, surfactant, binder, penetrant, lubricant, and flavoring agent; (b) Drug active ingredient, hydrophilic polymer, surfactant, binder, penetrant, lubricant, antioxidant, and flavoring agent; (c) Drug active ingredient, hydrophilic polymer, surfactant, penetrant, lubricant, antioxidant, and flavoring agent; (d) Drug active ingredient, hydrophilic polymer, surfactant, binder, penetrant, and lubricant; (i) Drug active ingredient, filler, penetrant, hydrophilic polymer, souring agent, and lubricant; (ii) Drug active ingredient, filler, hydrophilic polymer, and lubricant; (iii) Filler, penetrant, hydrophilic polymer, lubricant, and flavoring agent; (iv) Penetrant, hydrophilic polymer, and lubricant; (v) Filler, hydrophilic polymer, penetrant, and lubricant; (vi) Filler, penetrant, souring agent, and lubricant; (vii) Filler, penetrant, flavoring agent, and lubricant; or (viii) Filler, souring agent, and lubricant; In Scheme (1), the drug-containing layer is any one of the combinations from (a) to (d); In Scheme (2), the drug-containing layer is any one of the combinations from (i) to (v); In Scheme (3), the drug-containing layer is any one of the combinations from (a) to (d) and from (i) to (viii).

4. The osmotic pump tablet according to claim 3, wherein, The drug-containing layer is any one of the following combinations: (a) 63.0 wt% levodopa, 10.0 wt% hydroxypropyl cellulose, 10.0 wt% poloxamer, 5.0 wt% polyvinylpyrrolidone, 10.0 wt% sorbitol, 0.9 wt% aspartame, 0.1 wt% peppermint essence, and 1.0 wt% magnesium stearate; (b) 58.0 wt% levodopa, 15.0 wt% hydroxypropyl cellulose, 5.0 wt% poloxamer, 5.0 wt% polyvinylpyrrolidone, 15.0 wt% sorbitol, 0.9 wt% aspartame, 0.1 wt% peppermint essence, and 1.0 wt% magnesium stearate; (c) 58.0 wt% levodopa, 15.0 wt% hydroxypropyl cellulose, 5.0 wt% polyvinylpyrrolidone, 5.0 wt% poloxamer, 15.0 wt% sorbitol, 0.9 wt% aspartame, 0.1 wt% peppermint essence, and 1.0 wt% magnesium stearate; (d) 54.9 wt% levodopa, 3.16 wt% carbidopa, 15.0 wt% hydroxypropyl cellulose, 5.0 wt% polyvinylpyrrolidone, 14.87 wt% sorbitol, 5.0 wt% poloxamer, 0.9 wt% aspartame, 0.1 wt% peppermint essence, 0.1 wt% dibutylhydroxytoluene, and 1.0 wt% magnesium stearate; (e) 54.9 wt% levodopa, 3.16 wt% carbidopa, 15.0 wt% hydroxypropyl cellulose, 19.87 wt% mannitol, 0.9 wt% aspartame, 5.0 wt% poloxamer, 0.1 wt% peppermint essence, 0.1 wt% dibutylhydroxytoluene, and 1.0 wt% magnesium stearate; (f) 63.0 wt% levodopa, 11.0 wt% hydroxypropyl cellulose, 5.00 wt% polyvinylpyrrolidone, 10.0 wt% sorbitol, 10.0 wt% poloxamer, and 1.00 wt% magnesium stearate; (g) 63.0 wt% levodopa, 11.0 wt% hydroxypropyl cellulose, 5.00 wt% polyvinylpyrrolidone, 8.50 wt% sorbitol, 10.0 wt% poloxamer, 0.50 wt% colloidal silicon dioxide, and 2.00 wt% magnesium stearate; (i) 45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 5.00 wt% polyvinylpyrrolidone K29 / 32, 18.0 wt% mannitol, and 1.00 wt% magnesium stearate; (ii) 45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 5.00 wt% polyvinylpyrrolidone K29 / 32, 16.5 wt% mannitol, 0.50 wt% colloidal silicon dioxide, and 2.00 wt% magnesium stearate; ① 40.0 wt% levodopa, 10.8 wt% carbidopa monohydrate, 20.0 wt% microcrystalline cellulose, 18.7 wt% mannitol, 5.0 wt% hydroxypropyl methylcellulose, 5.0 wt% citric acid, and 0.5 wt% magnesium stearate; ②38.0 wt% levodopa, 50.0 wt% microcrystalline cellulose, 10.0 wt% hydroxypropyl methylcellulose, and 2.0 wt% magnesium stearate; ③40.0 wt% levodopa, 10.8 wt% carbidopa monohydrate, 31.0 wt% hydroxypropyl cellulose with an average molecular weight of 80,000, 12.7 wt% mannitol, 5.0 wt% citric acid, and 0.5 wt% magnesium stearate; ④45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 16.0 wt% mannitol, 5.0 wt% polyvinylpyrrolidone K30, 1.0 wt% aspartame, 1.0 wt% peppermint essence, and 1.0 wt% magnesium stearate; ⑤45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 17.0 wt% mannitol, 5.0 wt% polyvinylpyrrolidone K30, 1.0 wt% magnesium stearate, and 1.0 wt% aspartame; ⑥45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 17.0 wt% mannitol, 5.0 wt% polyvinylpyrrolidone K30, 1.0 wt% magnesium stearate, and 1.0 wt% aspartame; ⑦70.0 wt% levodopa, 9.0 wt% mannitol, 20.0 wt% polyvinylpyrrolidone K30, and 1.0 wt% magnesium stearate; ⑧20.0 wt% levodopa, 20.0 wt% carbidopa, 50.0 wt% hydroxypropyl cellulose, 4.0 wt% mannitol, 5.0 wt% aspartame, and 1.0 wt% magnesium stearate; ⑨45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 22.0 wt% mannitol, 0.9 wt% aspartame, 0.1 wt% peppermint essence, and 1.0 wt% magnesium stearate; ⑩19.5 wt% levodopa, 20.0 wt% carbidopa, 50.0 wt% mannitol, 10.0 wt% citric acid, and 0.5 wt% magnesium stearate; In Scheme (1), the drug-containing layer is any combination of (a) to (g); In Scheme (2), the drug-containing layer is any combination of (i) to (ii); In Scheme (3), the drug-containing layer is any combination of (a) to (f) and (i) to (ii) and ① to ⑩.

5. The osmotic pump tablet according to any one of claims 1 - 4, characterized in that In Scheme (1), Scheme (2), and Scheme (3), the tablet core independently further includes a boosting layer; the drug-containing layer and the boosting layer are stacked together in sequence to obtain a double-layer tablet core, and the coating film is wrapped outside the tablet core.

6. The osmotic pump tablet according to claim 5, wherein In Scheme (1), Scheme (2), and Scheme (3), the boosting layer independently meets one or more of the following conditions; (1) The mass ratio of the drug-containing layer to the boosting layer is 0.5:1 - 4:1, for example, 1.5:1 - 3.5:1; (2) The boosting layer contains one or more of a swelling agent, a penetrant, a binder, a lubricant, and a colorant, preferably a combination of a swelling agent, a penetrant, a binder, and a colorant, or a combination of a swelling agent, a penetrant, a binder, a lubricant, and a colorant.

7. The osmotic pump tablet according to claim 6, characterized in that, In Scheme (1), Scheme (2), and Scheme (3), the boosting layer independently satisfies one or more of the following conditions; (1) The swelling agent is selected from one or more of sodium carboxymethyl starch, hypromellose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carbomer, sodium alginate, κ-carrageenan, sodium carboxymethyl cellulose, or polyethylene oxide; for example, it is sodium carboxymethyl cellulose (7H4XF); preferably, based on the total mass of the boosting layer, the content of the swelling agent is 30-95 wt%, for example, 49.0-68.5 wt%; (2) The penetrant is selected from one or more of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose, lactose, starch, pregelatinized starch, dextrin, and microcrystalline cellulose, such as sorbitol or mannitol; preferably, based on the total mass of the boosting layer, the content of the penetrant is 5-70 wt%, for example, 10.0-30.0 wt%; (3) The binder is selected from one or more of methyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone, copovidone, and gelatin, such as hydroxypropyl cellulose (EXF); preferably, based on the total mass of the boosting layer, the content of the binder is 3-25 wt%, for example, 20 wt%; (4) The lubricant is one or more of stearic acid, magnesium stearate, magnesium stearyl fumarate, calcium stearate, sodium stearyl fumarate, polyethylene glycol, talc powder, etc., such as one or two of magnesium stearate and colloidal silica; preferably, based on the total mass of the boosting layer, the content of the lubricant is 0-7 wt%, but not 0, for example, 0-3 wt%, or for example, 0.5 wt%-1 wt%; (5) The colorant is one or more of iron oxide red, iron oxide yellow, iron oxide purple, and iron oxide black, such as iron oxide red; preferably, based on the total mass of the boosting layer, the content of the colorant is 0-2 wt%, but not 0, for example, 0.5 wt%.

8. The osmotic pump tablet according to claim 7, characterized in that, In Scheme (1), Scheme (2), and Scheme (3), the boosting layer independently satisfies any of the following combinations; (1) 49.0 wt% sodium carboxymethyl cellulose, 30.0 wt% sorbitol, 20.0 wt% hydroxypropyl cellulose, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate; (2) 68.5 wt% sodium carboxymethyl cellulose, 10.0 wt% sorbitol, 20.0 wt% hydroxypropyl cellulose, 0.5 wt% iron oxide red, 0.5 wt% colloidal silica, and 0.5 wt% magnesium stearate.

9. The osmotic pump tablet according to any one of claims 1-8, characterized in that, In Scheme (1), Scheme (2), and Scheme (3), the osmotic pump tablet independently further includes a barrier layer; the drug-containing layer, the boosting layer, and the barrier layer are stacked together in sequence to obtain a three-layer tablet core, and the coating film is wrapped outside the tablet core.

10. The osmotic pump tablet according to claim 9, characterized in that, In Scheme (1), Scheme (2) and Scheme (3), the isolation layer independently satisfies one or more of the following conditions: (1) The isolation layer independently contains one or more of ethyl cellulose, cellulose acetate, acrylic resin and microcrystalline cellulose, such as ethyl cellulose; (2) The mass ratio of the drug-containing layer to the isolation layer is (0.01 - 0.15):1, such as 0.05:1 - 0.1:

1.

11. The osmotic pump tablet according to any one of claims 1-10, characterized in that, In Scheme (1), Scheme (2) and Scheme (3), the coating film independently satisfies one or more of the following conditions: (1) The coating film contains a film-forming material and a pore-forming agent, or contains a film-forming material, a pore-forming agent and a plasticizer; Preferably, the film-forming material is selected from one or more of cellulose acetate, ethyl cellulose and acrylic resin, such as cellulose acetate, and for another example, cellulose acetate containing 39.8 wt% acetyl group; Preferably, based on the total mass of the coating film, the content of the film-forming material is 50 - 70 wt%, such as 50 wt% - 55 wt%; Preferably, the pore-forming agent is preferably copovidone, such as copovidone VA64; Preferably, based on the total mass of the coating film, the content of the pore-forming agent is 30 - 50 wt%, such as 45 wt% - 50 wt%; Preferably, the plasticizer is selected from one or more of polyethylene glycol, methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, tributyl acetylcitrate, glycerol acetate and castor oil, and for another example, triethyl citrate or polyethylene glycol 400; preferably, based on the total mass of the coating film, the content of the plasticizer is 0 - 20 wt%, such as 0 - 5 wt%, but not 0; (2) The tensile strength of the coating film is 1 - 10 Mpa; (3) The elongation at break of the coating film is 1.1 - 2.0; (4) The average thickness of the coating film is 100 ± 8 μm to 200 ± 10 μm; (5) The pore diameter of the drug release hole is 0.3 mm - 1.2 mm; (6) Based on the total weight of the osmotic pump tablet, the content of the coating film is 2 wt% - 10 wt%.

12. The osmotic pump tablet according to any one of claims 1 - 11, wherein In Scheme (1) and Scheme (2), the osmotic pump tablet further includes a drug-containing rapid-release outer coating; Preferably, the drug-containing rapid-release outer coating includes a drug active ingredient and a pharmaceutical excipient. The drug active ingredient contains one or more of levodopa, an ester of levodopa, a salt of levodopa and carbidopa; the pharmaceutical excipient includes one or more of a binder, an antioxidant, a plasticizer and a flavoring agent; the content of the drug active ingredient is preferably 70 - 90 wt%; the content of the binder is preferably 10 - 20.0 wt%; the content of the antioxidant is preferably 0.5 - 2.0 wt%; the content of the plasticizer is preferably 1 - 2 wt%; More preferably, the drug active ingredient is levodopa, carbidopa or a combination of the two; the pharmaceutical excipient is a combination of a binder, an antioxidant and a plasticizer or only a binder.

13. The osmotic pump tablet according to claim 12, wherein in the drug-containing immediate-release outer coating, the drug active ingredient comprises levodopa and / or carbidopa, and when there are two drug active ingredients, the mass ratio of levodopa to carbidopa is preferably 1:1 - 4:1; Preferably, in the drug-containing immediate-release outer coating, the masses of levodopa and carbidopa are respectively 12.5 mg and 12.5 mg, 18.75 mg and 10.8 mg, 25 mg and 25 mg, 37.5 mg and 37.5 mg, 50 mg and 50 mg, 62.5 mg and 62.5 mg, 75 mg and 75 mg, 87.5 mg and 87.5 mg, 100 mg and 100 mg, 125 mg and 125 mg, 150 mg and 150 mg, 200 mg and 200 mg, 25 mg and 12.5 mg, 50 mg and 25 mg, 75 mg and 37.5 mg, 100 mg and 50 mg, 150 mg and 75 mg, 200 mg and 100 mg, 50 mg and 12.5 mg, 100 mg and 25 mg, 150 mg and 37.5 mg, or 200 mg and 50 mg.

14. Use of an osmotic pump tablet according to any one of claims 1 - 13 in the preparation of a drug for treating motor symptom fluctuations in patients with advanced Parkinson's disease.

15. A method for preparing an osmotic pump tablet according to any one of claims 1 - 13, in Scheme (1), Scheme (2) and Scheme (3), the method for preparing the osmotic pump tablet independently comprises the following steps: S1. Prepare the drug-containing layer granules, which includes the following steps: mix the drug active ingredient and the excipient, and granulate to obtain the drug-containing layer granules; S2. Prepare the boosting layer granules, which includes the following steps: granulate at least one of the boosting layer excipients to obtain the boosting layer granules; S3. Prepare the double-layer tablet core, and compress the drug-containing layer granules and the boosting layer granules obtained in steps S1 and S2 to obtain the double-layer tablet core; S4. Prepare the osmotic pump tablet, wrap the tablet core with a coating film, and drill drug release holes to obtain it; S5. Optionally, after step S4, it further includes the step of wrapping a drug-containing immediate-release outer coating outside the osmotic pump tablet; Optionally, after step S3 and before step S4, it further includes the step of preparing a separation layer; the step of preparing the separation layer includes compressing the separation layer material and the double-layer tablet core; Step S5 is a must in Scheme (3).

16. The preparation method of the osmotic pump tablet according to claim 15, wherein, In Scheme (1), Scheme (2) and Scheme (3), the method for preparing the osmotic pump tablet independently meets one or more of the following conditions: (1) In steps S1 and S2, before the mixing, it includes the step of screening each component; the screening is preferably carried out through a 40-mesh sieve; (2) In steps S1 and S2, the granulation is independently dry granulation, wet granulation or fluidized bed granulation; when wet granulation is adopted, it is preferably dried by a fluidized bed after granulation; (3) After the granulation in steps S1 and S2, it preferably includes the step of sizing; the sizing is preferably carried out through a 1.2-mm sieve. (4) In step S3, the tablet press die used in the tablet pressing method is preferably a 7.0 mm round punch; (5) The drug release hole is obtained by laser drilling or mechanical drilling.

17. A method for using an osmotic pump tablet according to any one of claims 1-13, characterized in that, The osmotic pump tablet is used in combination with the oral retention device or the oral drug delivery device.

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