Osmotic pump tablet as well as preparation method and application thereof

Abstract

The invention relates to an osmotic pump tablet as well as a preparation method and application thereof. 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 comprises a drug-containing layer, the drug-containing layer comprises active pharmaceutical ingredients, a hydrophilic polymer and a surfactant, the hydrophilic polymer comprises hydroxypropyl cellulose, and the surfactant comprises poloxamer; or the drug-containing layer comprises a drug active ingredient and a hydrophilic polymer, but does not contain a surfactant; the hydrophilic polymer is prepared from povidone K29 / 32; or the osmotic pump tablet contains the drug-containing quick-release outer coating, the drug-containing quick-release outer coating contains the active pharmaceutical ingredient and the pharmaceutic adjuvant, and the pharmaceutic adjuvant is an adhesive. The invention further provides a preparation method and application of the compound. The osmotic pump tablet disclosed by the invention is high in drug loading capacity and can well play a treatment effect.

Description

Technical Field

[0001] The present disclosure relates to an osmotic pump tablet and its preparation method and application. Background Art

[0002] Many drug active ingredients (APIs), including levodopa (LD), carbidopa (CD), baclofen, acyclovir, valacyclovir, ganciclovir, metformin, gabapentin, etc., have an absorption window limited to the upper gastrointestinal tract. Incorporating these APIs into conventional sustained-release dosages not only results in reduced bioavailability but also fails to achieve extended therapeutic coverage. Therefore, many techniques have been disclosed in the prior art to prolong their residence time in the stomach. These techniques are: dilation (USP4,735,804, 5,002,772, and 6,685,962), swelling (USP 4,434,153, 5,750,585, 5,972,389, 6,120,803, 6,660,300B1, US2007 / 0196396 A1, and USP 9,439,851), floating (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), etc. The success of the above techniques is very limited, especially when the oral dosage forms using these techniques are administered in a fasting state. Therefore, a new controlled-release system or drug controlled-release system is needed, which can provide long-term exposure to these drug active ingredients and whose absorption window is limited to the upper gastrointestinal tract. By combining an oral retention device with these drugs to form a pharmaceutical device composition, an oral retention drug delivery system can be formed, which can provide long-term exposure to these drugs with an absorption window limited to the upper gastrointestinal tract.

[0003] In addition, for local drug delivery to the oral mucosa, common liquid or semi-solid preparations such as sprays, mouthwashes, and ointments have a short residence time in the oral cavity and cannot achieve a sustained drug delivery effect. Therefore, a drug delivery system that can provide long-term exposure of drug components is needed, which is suitable for drugs with an absorption window in the upper gastrointestinal tract or drugs that require local oral drug delivery. By loading drugs into a drug delivery device and combining it with a fixing device and then fixing it in the oral cavity, a drug controlled-release system is formed to provide long-term exposure to drugs with an absorption window limited to the upper gastrointestinal tract.

[0004] 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 the electrically controlled system claimed in the patent are difficult to implement. CN105873631A discloses an oral drug delivery device, which requires an electronic pump or a mechanical pump as an external power to achieve drug delivery. In addition, CN1925823A discloses a tooth bracket for attaching fluoride pills to teeth to improve the treatment or prevention of 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 patent applications that have been published may require external power, or may rely on dentures, braces, etc. to achieve, or may not involve drug absorption at the absorption end in the upper gastrointestinal tract.

[0005] 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 concentration. The oral retention device has taken 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-matching component 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.

[0006] 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 the facial appearance when worn.

[0007] Osmotic pump tablets are an ideal type of orally controlled-release preparation to date for drug active ingredients whose absorption window is restricted to the upper gastrointestinal tract. Early osmotic pump tablets were single-layer core osmotic pump tablets, generally composed of a water-soluble drug core, a coating film, and a drug release hole. When in an aqueous environment, water enters the core through the semi-permeable controlled-release membrane, hydrating the core to form a drug solution, and then an internal and external osmotic pressure difference is generated. Driven by the osmotic pressure difference, water continuously enters the core through the semi-permeable coating film, driving the drug solution to be released outward from the drug release hole. Single-layer core osmotic pump tablets can be used for controlled-release preparations of large-dose water-soluble APIs. However, for water-insoluble drugs, the osmotic pressure generated by the drug itself is low. Although the addition of osmotic agents can provide osmotic pressure, the solid drug powder tends to settle downward, and it is difficult to obtain an ideal large-dose osmotic pump tablet for water-insoluble drugs through a single-layer core osmotic pump tablet. The drug release is non-constant and there is a lot of residue in the end.

[0008] Compared with single-layer core osmotic pump tablets, double-layer core osmotic pump tablets are composed of a drug-containing layer and a boosting layer, and can provide zero-order constant-rate drug release for both water-soluble and water-insoluble drugs, and the drug release is complete (the drug release amount is greater than 90%). Double-layer core osmotic pump tablets are the most mature and suitable dosage form for industrial production of osmotic pump tablets for current drugs, especially water-insoluble drugs. However, the drug release amount is limited by the drug loading and the permeability of the controlled-release membrane, and the drug loading and drug release amount are often not high. For conventional double-layer core osmotic pump tablets, when pushing drugs, especially large-dose drugs, due to the limitation of their own structure, the interface between the drug-containing layer and the boosting layer cannot be maintained, resulting in the boosting layer passing through the drug release hole before the drug-containing layer in the middle and late stages of drug release, the drug release rate changes and a large amount of drug remains.

[0009] There is also a high-dose osmotic pump tablet. To achieve a high-throughput drug release effect, it is a great challenge to the physicochemical properties of the controlled-release membrane. On the one hand, the membrane needs to have high mechanical strength to resist the resistance caused by the high-loaded drug paste passing through the drug release hole, thereby avoiding the rupture of the membrane during the drug release process. At the same time, the membrane needs to have good medium permeability so that water can quickly enter the core through the controlled-release membrane, and the drug can be quickly released after the drug-containing layer is hydrated. Currently, there is no high-dose osmotic pump tablet suitable for drug active ingredients whose absorption window is restricted to the upper gastrointestinal tract, and this problem needs to be solved urgently. Summary of the Invention

[0010] In order to overcome the current controlled-release drugs that cannot provide a long-term and stable plasma curve of drug active ingredients; and to avoid the precipitation of cellulose acetate during the coating process of the controlled-release membrane, thereby solving the defects of uneven coating and unstable drug release, a controlled-release system of drug active ingredients and its preparation method are provided.

[0011] Therefore, on the one hand, the present disclosure relates to a controlled-release dosage form with an absorption window in the upper gastrointestinal tract, and the controlled-release dosage form includes a controlled-release platform and a retention platform;

[0012] The controlled release platform (ERP) is a pharmaceutical composition, which comprises a tablet core and a coating film. The tablet core contains a drug-containing layer, and the coating film contains cellulose acetate and copovidone. The weight of the cellulose acetate is 50-70% of the weight of the coating film; the weight of the copovidone is 30-50% of the weight of the coating film;

[0013] The function of the retention platform is to hold the controlled release platform in the oral cavity. At least one end of the retention platform is connected with a cover body, which can make the controlled release platform stay in the retention platform.

[0014] To solve the technical problem of the short residence time of the drug active ingredient in the stomach, which leads to low bioavailability, on the other hand, the present disclosure relates to a new oral retention device that can make the tablet stay in the oral cavity and is not easy to fall off. Specifically, the present disclosure provides an oral retention device in which the insertion method of the tablet is from back to front. Because the back side is close to the throat and is blocked by oral tissues such as the apex of the buccal fat pad and the pterygomandibular fold, the tablet will not fall off in the oral device and will not cause asphyxia due to accidental swallowing.

[0015] The oral retention device is similar to the above-mentioned retention platform but does not contain a cover body. It includes a tooth-engaging member and a drug-carrying member. The tooth-engaging member is connected to the drug-carrying member. Among them, the tooth-engaging member is used to bridge the teeth in the oral cavity and match with the teeth, and the drug-carrying member can accommodate at least one tablet and is used to make the tablet stay in the oral cavity.

[0016] In some embodiments, the tablet in the oral retention device can be the retention platform or the pharmaceutical composition or the osmotic pump tablet in the present disclosure.

[0017] In some embodiments, the copovidone is prepared by the following method, which includes the following steps: polymerize vinylpyrrolidone and vinyl acetate, and the weight ratio of vinylpyrrolidone to vinyl acetate is 40:60-80:20. Preferably, the weight ratio of vinylpyrrolidone to vinyl acetate is 50:50-70:30. More preferably, the weight ratio of vinylpyrrolidone to vinyl acetate is 60:40.

[0018] In some embodiments, the retention platform includes a personalized retention component and a drug fixation component. The drug fixation component can fix the controlled release platform, and the personalized retention component can maintain the drug fixation component in the oral cavity. More preferably, the drug fixation component is one or more reservoirs. In one embodiment, the reservoir is a basket structure. In another embodiment, the cross-sectional shape of the reservoir is polygonal, circular closed-loop or circular open-loop, or a combination thereof.

[0019] In some embodiments, at least one end of the reservoir is connected to a cover, which can retain the controlled release platform within the reservoir; more preferably, the cover is a strip.

[0020] In some embodiments, the retention assembly can conform to any one or more teeth in the oral cavity. Preferably the mandibular permanent teeth. More preferably the mandibular molars. Most preferably the mandibular second molar and the molars before and after it.

[0021] The retention assembly can be customized to conform to, wrap around, snap into, or insert into the entire maxillary teeth or the entire mandibular permanent teeth; preferably wrap around, snap into, or insert into the mandibular permanent teeth; more preferably wrap around the mandibular molars; most preferably wrap around, snap into, or insert into the mandibular second molar and the adjacent first molar and second premolar.

[0022] When the retention platform is referred to as an oral retention device, the customized retention assembly can be a tooth conforming member, and the drug fixation assembly is referred to as a drug carrying member.

[0023] In some embodiments, the tooth conforming member and the drug carrying member are connected to each other at their respective sides.

[0024] In some embodiments, the tooth conforming member can conform to any one or more teeth in the oral cavity.

[0025] In some embodiments, the length of the tooth conforming member is the length of 2 - 5 teeth.

[0026] In some embodiments, the teeth are mandibular permanent teeth, preferably mandibular molars, more preferably any of the following combinations: (i) the first and second molars of the mandible; (ii) the first molar, the second molar, and the second premolar; (iii) the first molar, the second molar, and the third molar; or (iv) the first molar, the second molar, the third molar, and the second premolar.

[0027] In some embodiments, the tooth conforming member wraps around, embeds in, snaps into, or inserts into the teeth that it conforms to.

[0028] In some embodiments, the drug carrying member is a network structure or a non - network structure.

[0029] In some embodiments, the cross - sectional shape of the drug carrying member is a circular, oval, polygonal, or irregular closed - loop or open - loop structure.

[0030] In some embodiments, the drug carrying member includes at least one ring body and at least one limiting member, or, the drug carrying member is composed of at least one limiting member; wherein, the ring body has an opening for inserting a tablet, and the structure of the limiting member is used to limit the tablet within the drug carrying member.

[0031] In some embodiments, the ring body is an open ring body or a closed ring body.

[0032] In some embodiments, the ring body is a circular, oval, polygonal or irregular closed or open ring body.

[0033] In some embodiments, the number of the ring bodies is one, and the ring body is located on the side of the molar in the horizontal direction formed by the molar and the incisor.

[0034] In some embodiments, the limiting member is in an arc-shaped hollow or solid shape.

[0035] In some embodiments, the limiting member is formed by connecting a closed ring body and a semi-circle perpendicular to the closed ring body.

[0036] In some embodiments, the limiting member is adjacent to the ring body, or the limiting member is arranged at an interval from the ring body. Preferably, the adjacency is integrally formed or connected together through a connecting structure.

[0037] In some embodiments, the number of the limiting members is one.

[0038] In some embodiments, the limiting member is located on the side of the incisor in the horizontal direction formed by the molar and the incisor.

[0039] In some embodiments, the opening faces the molar in the horizontal direction formed by the molar and the incisor, for inserting the tablet in the horizontal direction from the molar to the incisor; or, the opening is arranged in a direction perpendicular to the horizontal direction, and the tablet is inserted from top to bottom in a direction perpendicular to the horizontal direction; or, the opening faces the buccal side in a direction perpendicular to the horizontal direction, and the tablet is inserted from the buccal side to the lingual side in a direction perpendicular to the horizontal direction.

[0040] The controlled release platform of the present disclosure is an osmotic pump delivery system including 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 a constant release of LD / CD in the oral cavity, which is in sharp contrast to the matrix extended release system. The matrix extended release system is sensitive to conditions in the oral cavity such as pH, saliva availability, and the voluntary or involuntary friction of the hydrated matrix tablet by the tongue.

[0041] The Retention Enabling Platform (REP) of the present disclosure is a personalized customized ERP retainer that can fasten the ERP in the oral cavity. Therefore, the LD / CD can be released near the throat and easily absorbed into the stomach. The REP is a REP with safety features that can prevent accidental blockage of the controlled release system. In the present disclosure, the "personalized customization" refers to preparing the retention platform or retention assembly that can fasten the ERP in the oral cavity and conform to the shape of one or more teeth, or the entire maxillary teeth or the entire mandibular teeth of the patient according to the shape of the patient's teeth.

[0042] Another aspect of the present disclosure relates to a method for preparing the controlled release dosage form. The method for preparing the retention platform or oral retention device includes 3D printing, injection molding, or impression molding. Combining oral scanning, CAD / CAM design, and the preparation method can accurately and quickly generate the REP according to the individual oral scan image.

[0043] Among them, the working principle of 3D printing is basically the same as that of an ordinary printer, except for the printing materials. The printing materials of an ordinary printer are ink and paper, while the 3D printer is equipped with different "printing materials" such as metals, ceramics, plastics, and sands. After the printer is connected to the computer, the "printing materials" can be stacked layer by layer under computer control, and finally the blueprint on the computer can be turned into a physical object. 3D printing refers to the technical principle of an ordinary printer, and the process of layer-by-layer processing is very similar to inkjet printing. This printing technology is called 3D stereolithography technology. There are many different technologies in 3D printing. Their differences lie in the way of available materials and the creation of components in different layers. The commonly used materials for 3D printing are nylon fiberglass, polylactic acid, ABS resin, durable nylon materials, gypsum materials, aluminum materials, metal titanium, titanium alloy, stainless steel, silver plating, gold plating, cobalt-chromium alloy, cobalt-chromium-molybdenum alloy, or rubber-like materials. The advantages of 3D printing are that the operation can be automated, the production speed is fast, the design blueprint in the computer can be directly and relatively accurately turned into a physical model, and it is also suitable for small-scale customized production and manufacturing.

[0044] Among them, the 3D printing includes the following steps:

[0045] (1) In the design software, preferably in 3Shape Dental System, add the saved scheme of the drug-loaded component, and assemble it with the scheme of the tooth-fitting component into an integrated scheme of the oral retention device, and export a 3D-printable file;

[0046] (2) Import the 3D-printable file into a 3D printer and print the oral retention device; the 3D printing preferably uses the laser sintering process;

[0047] Preferably, before the step (1), the following steps are further included: (0) In the software SolidWorks, design the scheme of the drug-carrying component according to the data of the tablet size and save it; and / or, in the design software 3Shape Dental System, design the scheme of the tooth-fitting component according to the data of the tooth size of the subject;

[0048] More preferably, the data of the tablet size and / or the data of the teeth of the subject are obtained by scanning with a scanner, and the scanner is preferably 3Shape scanner or Medit i500 scanner.

[0049] In some embodiments, use the "3Shape " intraoral scanner to scan the size data of the tablet, and then import the data into the "SolidWorks" software to design the scheme of the drug-carrying component that can hold the drug part, create and save this scheme as a "standard accessory" file; use the "3Shape " intraoral scanner to scan the teeth of the subject, import the data into the "3Shape Dental System" software, and design the tooth-fitting component according to the tooth data; on the "3Shape DentalSystem" software, add the "standard accessory" and assemble it with the tooth-fitting component into an integrated oral retention device, and export a file that can be 3D printed; import the file that can be 3D printed into a 3D printer and print the oral retention device. The 3D printing preferably uses the selective laser sintering process.

[0050] Injection molding, also known as injection molding, is a molding method that combines injection and molding. That is, at a certain temperature, the fully molten polymer material is stirred by a screw and injected into the mold cavity under high pressure. After cooling and solidification, the molded product is obtained. This method is suitable for mass production of parts with complex shapes and is one of the important processing methods. The advantages of the injection molding method are fast production speed, high efficiency, automation of operation, a variety of colors and patterns, the shape can range from simple to complex, the size can range from large to small, and the product size is accurate, the product is easy to update, and it can form parts with complex shapes. Injection molding is suitable for forming and processing fields such as mass production and products with complex shapes.

[0051] Among them, the injection molding includes the following steps:

[0052] (1) Prepare a tooth-fitting component model according to the tooth model;

[0053] (2) Prepare a drug-carrying component model according to the tablet size;

[0054] (3) Obtain an integrated oral retention device model of the tooth-fitting component and the drug-carrying component;

[0055] (4) Prepare a personalized oral retention device by traditional injection molding process;

[0056] In some embodiments, the tooth model is prepared by traditional impression-taking techniques or obtained by oral scanning technology to acquire the tooth data of the subject and then printed.

[0057] In some embodiments, the materials of the tooth fitting member model, the drug-carrying member model, and the oral retention device model are dental wax, and / or the material of the tooth model is gypsum or resin.

[0058] For impression molding, first prepare a drug fixation component suitable for the controlled release platform. Secondly, process an oval thermoplastic sheet by conventional techniques. Finally, for the preparation of a personalized REP, heat a thermoplastic sheet in hot water at about 70 °C to make it soften 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 to completely wrap the teeth and form a retention component that perfectly fits the teeth. Then quickly embed the drug fixation component onto the uncured retention component and cool it to cure into a personalized retention platform (REP). Water can be briefly sprayed to further accelerate cooling. Wait for the personalized retention platform to cool and return to its original opaque hard sheet state, and then take out the cooled personalized retention platform from the oral cavity.

[0059] In some embodiments, the method for preparing the oral retention device of the present disclosure is impression molding, which includes:

[0060] Design a drug-carrying member according to the tablet size; prepare a tooth fitting member with polycaprolactone (PCL) as the material and a drug-carrying member with cobalt-chromium alloy as the material; assemble the tooth fitting member and the drug-carrying member into a complete oral retention device.

[0061] In some embodiments, first prepare a drug-carrying member capable of loading an osmotic pump tablet by traditional injection molding process; then heat and soften a thermoplastic sheet to prepare a tooth fitting member, and at the same time, fit the softened tooth fitting member with the drug-carrying member, and after cooling, form an integrated oral retention device and take it out from the oral cavity.

[0062] In some embodiments, the retention platform or the oral retention device is prepared from one or more oral stability materials, and the oral stability materials include oral stability metals and thermoplastic elastomers.

[0063] In some embodiments, the orally stable metal comprises or is selected from dental titanium, stainless steel, cobalt-chromium alloy, cobalt-chromium-molybdenum alloy, nickel-chromium alloy, or noble metal, and the thermoplastic elastomer comprises 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 a copolymer of any two or more of the above, or a physical combination thereof.

[0064] In some embodiments, the tooth-engaging member and the drug-carrying member are made of cobalt-chromium alloy.

[0065] The pharmaceutical composition or the upper gastrointestinal (UGI) controlled-release drug delivery system described in the present disclosure includes forms such as a single-layer basic osmotic pump, a bilayer push-pull osmotic pump, and a bilayer push-pull osmotic pump with a fast-release drug outer coating, etc., but is different from the osmotic pumps in the prior art.

[0066] In the controlled-release dosage form of the present disclosure as described above, preferably, in the controlled-release platform, the drug-containing layer contains a drug active ingredient and excipients.

[0067] In some embodiments, the drug active ingredient is one or more of levodopa or its ester or its salt, carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin; or one or two of levodopa or its ester and carbidopa. Among them, the ester of levodopa can be an alkyl ester of levodopa or a deuterated alkyl ester of levodopa, such as levodopa methyl ester hydrochloride. The salt of levodopa is, for example, levodopa ethyl ester hydrochloride. The drug active ingredient is, for example, selected from antifungal drugs and antitumor drugs. The antifungal drugs are, for example, selected from one or more of nystatin, fluconazole, posaconazole, isavuconazole, voriconazole, anidulafungin, caspofungin, and micafungin. The antitumor drugs are, for example, selected from one or more of 5-fluorouracil, paclitaxel, and capecitabine.

[0068] In some embodiments, the drug active ingredient contains levodopa and / or carbidopa.

[0069] In some embodiments, the excipients are one or more of fillers, osmotic agents, hydrophilic polymers, binders, lubricants, preservatives, flavoring agents, acidifying agents, and antioxidants. More preferably, the excipients are one or more of fillers, osmotic agents, hydrophilic polymers, binders, lubricants, and preservatives. Even more preferably, the excipients are fillers, osmotic agents, hydrophilic polymers, binders, lubricants, and preservatives.

[0070] In one embodiment, when the pharmaceutically active ingredient contains levodopa, the content of levodopa is 20 - 70 wt% based on the total weight of the drug-containing layer. In another embodiment, when the active ingredient contains carbidopa, the content of carbidopa is 0 - 20 wt% but not 0% based on the total weight of the drug-containing layer.

[0071] In one embodiment, the pharmaceutically active ingredient contains levodopa, and the content of levodopa is 30 - 50 wt% based on the total weight of the drug-containing layer. In another embodiment, the active ingredient contains carbidopa, and the content of carbidopa is 1 - 10 wt% based on the total weight of the drug-containing layer.

[0072] Preferably, in the above-mentioned drug-containing layer, when the excipient contains a filler, the filler is one or more of microcrystalline cellulose, hydroxypropyl cellulose, and mannitol. The content of the filler is preferably 0 - 50 wt% but not 0% based on the total weight of the drug-containing layer.

[0073] In another embodiment, when the excipient contains a permeation agent, the permeation 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 permeation agent is preferably 0 - 50 wt% but not 0% based on the total weight of the drug-containing layer.

[0074] In another embodiment, when the excipient contains a hydrophilic polymer, the hydrophilic polymer is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone (such as 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% based on the total weight of the drug-containing layer.

[0075] 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% based on the total weight of the drug-containing layer.

[0076] Preferably, the pharmaceutical composition further includes a permeation-pushing layer. The permeation-pushing layer preferably contains a hydrophilic polymer, a permeation agent, and a binder, and optionally a lubricant and / or a colorant. The permeation-pushing layer and the drug-containing layer are components of a double-layer tablet core, and the coating film is wrapped outside the tablet core. This pharmaceutical composition can be a type of osmotic pump controlled-release drug delivery system, namely a double-layer push-pull osmotic pump.

[0077] As a pharmaceutical composition of a double-layer push-pull osmotic pump, preferably, the hydrophilic polymer in the osmotic push layer is κ-carrageenan, sodium carboxymethyl cellulose or polyethylene oxide. The molecular weight of the hydrophilic polymer is preferably 75,000 - 7,500,000. Based on the total weight of the osmotic push layer, the content of the hydrophilic polymer is preferably 25 - 85 wt%.

[0078] In one embodiment, the osmotic agent in the osmotic pump push layer 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 osmotic push layer, the content of the osmotic agent is preferably 5 - 65 wt%.

[0079] In another embodiment, the binder in the osmotic pump push layer is one or more of methyl cellulose, hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone and gelatin. Based on the total weight of the osmotic push layer, the content of the binder is preferably 3 - 20 wt%.

[0080] In another embodiment, when the osmotic pump push layer contains a lubricant, the lubricant is one or more of magnesium stearate, magnesium stearyl fumarate, talc and colloidal silica. Based on the total weight of the osmotic push layer, the weight percentage of the lubricant is preferably 0 - 2 wt% but not 0%.

[0081] In another embodiment, when the osmotic push layer contains a colorant, the colorant is one or more of iron oxide red, iron oxide yellow and iron oxide black. Based on the total weight of the osmotic push layer, the weight percentage of the colorant is 0 - 5 wt% but not 0%.

[0082] Preferably, the osmotic push layer contains sodium carboxymethyl cellulose, sorbitol, povidone, iron oxide red and magnesium stearate; or contains sodium carboxymethyl cellulose, hydroxypropyl cellulose, sorbitol, iron oxide red and magnesium stearate; preferably consists of sodium carboxymethyl cellulose, povidone K30, sorbitol, iron oxide red and magnesium stearate; or consists of sodium carboxymethyl cellulose, hydroxypropyl cellulose, sorbitol, iron oxide red and magnesium stearate. More preferably, the sodium carboxymethyl cellulose is sodium carboxymethyl cellulose 7H4XF or 9H4XF.

[0083] In a certain embodiment, based on the total weight of the osmotic push layer, the osmotic push layer contains 25 - 85 wt% of sodium carboxymethyl cellulose, 5 - 65 wt% of sorbitol, 3 - 20 wt% of povidone, 0 - 5 wt% of iron oxide red and 0.5 - 2 wt% of magnesium stearate; or contains 25 - 85 wt% of sodium carboxymethyl cellulose, 5 - 65 wt% of sorbitol, 3 - 20 wt% of hydroxypropyl cellulose, 0 - 5 wt% of iron oxide red and 0.5 - 2 wt% of magnesium stearate.

[0084] In another embodiment, based on the total weight of the osmotic push layer, the osmotic push layer contains 55 wt% of sodium carboxymethylcellulose, 39.0 wt% of sorbitol, 5.0 wt% of polyvinylpyrrolidone, 0.5 wt% of iron oxide red, and 0.5 wt% 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 carboxymethylcellulose, 34.0 wt% of sorbitol, 10.0 wt% of polyvinylpyrrolidone K30, 0.5 wt% of iron oxide red, 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 carboxymethylcellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red, and 0.5 wt% of magnesium stearate.

[0087] In another embodiment, based on the total weight of the osmotic push layer, the osmotic push layer contains 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose, 0.5 wt% of iron oxide red, and 0.5 wt% of magnesium stearate.

[0088] In some preferred embodiments, there is an additional drug-containing rapid-release outer coating outside the coating film of the pharmaceutical composition. Thus, a three-layer structure is formed with the inner layer being the tablet core, the middle layer being the coating film, and the outer layer being the outer coating.

[0089] More preferably, the drug-containing rapid-release outer coating includes a drug active ingredient and excipients. The drug active ingredient contains levodopa and / or carbidopa, and the excipients are one or more of hydroxypropyl cellulose, aspartame, and peppermint essence.

[0090] In one embodiment, based on the total weight of the drug-containing rapid-release outer coating, when the drug active ingredient is levodopa, the content of levodopa is 0 - 75 wt% but not 0%, preferably 23.78 - 75 wt%. When the drug active ingredient is carbidopa, the content of carbidopa is 0 - 93 wt% but not 0%, preferably 26.85 wt% - 93 wt%. When the excipient of the outer coating contains hydroxypropyl cellulose, the content of hydroxypropyl cellulose is 2 - 20 wt%, preferably 10 wt%. When the excipient of the outer coating contains aspartame, the content of aspartame is 0 - 5 wt%, preferably 0.9 - 5 wt%. When the excipient of the outer coating contains peppermint essence, the content of peppermint essence is 0 - 5 wt%, preferably 0.1 wt%.

[0091] Further more preferably, the weight of the coating film is not less than 2.0% of the weight of the tablet core. There are one to more orifices on the coating film, and the diameter of the orifice is preferably 0.5 mm - 1.0 mm; more preferably 0.5 mm, 0.75 mm and 1.0 mm. Preferably, the weight of the coating film is 2.0 - 15.0% of the weight of the tablet core. More preferably, the weight of the coating film is 4.0 - 8.0% of the weight of the tablet core.

[0092] Preferably, in one embodiment, the pharmaceutical composition consists of a drug-containing layer and a coating film. In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pushing layer and a coating film. In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pushing layer, a coating film and an outer coating.

[0093] 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 povidone K30. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropyl cellulose, mannitol, povidone K30, magnesium stearate, peppermint essence 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, hydroxypropyl cellulose, mannitol, aspartame and magnesium stearate. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropyl cellulose, mannitol, povidone K30, magnesium stearate, peppermint essence and aspartame. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropyl cellulose, mannitol, povidone K30, magnesium stearate and aspartame. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropyl cellulose, mannitol, magnesium stearate, peppermint essence and aspartame. In another embodiment, the drug-containing layer consists of levodopa, hydroxypropyl cellulose, povidone, mannitol and magnesium stearate.

[0094] Preferably, the osmotic push layer is composed of sodium carboxymethylcellulose, polyvinylpyrrolidone, sorbitol, iron oxide red, and magnesium stearate, or is composed of sodium carboxymethylcellulose, hydroxypropyl cellulose, sorbitol, iron oxide red, and magnesium stearate. Preferably, the sodium carboxymethylcellulose is sodium carboxymethylcellulose 7H4XF or 9H4XF. The polyvinylpyrrolidone is preferably polyvinylpyrrolidone K30. The hydroxypropyl cellulose is hydroxypropyl cellulose EXF.

[0095] In one embodiment, the outer coating is composed of levodopa, carbidopa, hydroxypropyl cellulose, aspartame, and mint essence; or is composed of levodopa, carbidopa, hydroxypropyl cellulose, and aspartame. In another embodiment, the outer coating is composed of carbidopa, hydroxypropyl cellulose, and aspartame. In another embodiment, the outer coating is composed of levodopa, hydroxypropyl cellulose, and mint essence. As is well known to those skilled in the art, the above "comprising" can be replaced with "consisting of".

[0096] Preferably, based on the total weight of the drug-containing layer,

[0097] The drug-containing layer is composed of 40 wt% levodopa, 10.8 wt% carbidopa, 20 wt% microcrystalline cellulose, 18.7 wt% mannitol, 5 wt% citric acid, 5 wt% sodium hydroxypropylmethylcellulose, and 0.5 wt% magnesium stearate; or

[0098] The drug-containing layer is composed of 38 wt% levodopa, 50 wt% microcrystalline cellulose, 10 wt% hydroxypropylmethylcellulose, and 2 wt% magnesium stearate; or

[0099] The drug-containing layer is composed of 19.5 wt% levodopa, 20 wt% carbidopa, 50 wt% mannitol, 10 wt% citric acid, and 0.5 wt% magnesium stearate; or

[0100] 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

[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% polyvinylpyrrolidone K30; or

[0102] The drug-containing layer is composed of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 16 wt% mannitol, 5 wt% polyvinylpyrrolidone K30, 1 wt% magnesium stearate, 1 wt% mint essence, and 1 wt% aspartame; or

[0103] The drug-containing layer is composed of 70 wt% levodopa, 9 wt% mannitol, 20 wt% povidone K30 and 1 wt% magnesium stearate; or

[0104] The drug-containing layer is composed of 20 wt% levodopa, 20 wt% carbidopa, 50 wt% hydroxypropyl cellulose, 4 wt% mannitol, 5 wt% aspartame and 1 wt% magnesium stearate; or

[0105] The drug-containing layer is composed of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 17 wt% mannitol, 5 wt% povidone K30, 1 wt% magnesium stearate and 1 wt% aspartame; or

[0106] The drug-containing layer is composed of 62.5 wt% levodopa, 31 wt% hydroxypropyl cellulose, 4.5 wt% mannitol, 1 wt% magnesium stearate, 0.1 wt% peppermint essence and 0.9 wt% aspartame; or

[0107] The drug-containing layer is composed of 46.9 wt% levodopa, 31 wt% hydroxypropyl cellulose, 20.1 wt% mannitol, 1 wt% magnesium stearate, 0.1 wt% peppermint essence and 0.9 wt% aspartame; or

[0108] The drug-containing layer is composed of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 17 wt% mannitol, 5 wt% povidone K30, 1 wt% magnesium stearate and 1 wt% aspartame; or

[0109] The drug-containing layer is composed of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 12 wt% mannitol, 5 wt% povidone K30, 1 wt% magnesium stearate, 5 wt% peppermint essence and 1 wt% aspartame; or

[0110] The drug-containing layer is composed of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 22 wt% mannitol, 1.0 wt% magnesium stearate, 0.1 wt% peppermint essence and 0.9 wt% aspartame.

[0111] More preferably, based on the total weight of the coating film, the coating film is composed of 50 wt% cellulose acetate and 50 wt% copovidone VA64; the coating film is composed of 70 wt% cellulose acetate and 30 wt% copovidone VA64; the coating film is composed of 60 wt% cellulose acetate and 40 wt% copovidone VA64.

[0112] 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.

[0113] Preferably, based on the total weight of the osmotic push layer,

[0114] the osmotic push layer is composed of 55 wt% sodium carboxymethylcellulose 7H4XF, 5 wt% polyvinylpyrrolidone K30, 39 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate; or

[0115] the osmotic push layer is composed of 55 wt% sodium carboxymethylcellulose 7H4XF, 10 wt% polyvinylpyrrolidone K30, 34 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate; or

[0116] the osmotic push layer is composed of 85 wt% sodium carboxymethylcellulose, 3 wt% polyvinylpyrrolidone K30, 5 wt% sorbitol, 5 wt% iron oxide red, and 2 wt% magnesium stearate; or

[0117] the osmotic push layer is composed of 25 wt% sodium carboxymethylcellulose, 9.5 wt% polyvinylpyrrolidone K30, 65 wt% sorbitol, and 0.5 wt% magnesium stearate; or

[0118] the osmotic push layer is composed of 60 wt% sodium carboxymethylcellulose 7H4XF, 10 wt% polyvinylpyrrolidone K30, 26 wt% sorbitol, 2 wt% iron oxide red, and 2 wt% magnesium stearate; or

[0119] the osmotic push layer is composed of 40 wt% sodium carboxymethylcellulose 7H4XF, 20 wt% polyvinylpyrrolidone K30, 36 wt% sorbitol, 3.5 wt% iron oxide red, and 0.5 wt% magnesium stearate; or

[0120] the osmotic push layer is composed of 55 wt% sodium carboxymethylcellulose 9H4XF, 5 wt% polyvinylpyrrolidone K30, 39 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate; or

[0121] the osmotic push layer is composed of 55 wt% sodium carboxymethylcellulose 7H4XF, 10 wt% hydroxypropylcellulose, 34 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5% magnesium stearate.

[0122] Preferably, based on the total weight of the outer coating,

[0123] the outer coating is composed of 23.78 wt% levodopa, 64.22 wt% carbidopa, 10 wt% hydroxypropylcellulose, 1 wt% aspartame, and 1 wt% mint essence; or

[0124] the outer coating is composed of 93 wt% carbidopa, 2 wt% hydroxypropylcellulose, and 5 wt% aspartame; or

[0125] The outer coating consists of 75 wt% levodopa, 20 wt% hydroxypropyl cellulose, and 5 wt% peppermint essence; or

[0126] 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% peppermint essence; or

[0127] The outer coating consists of 24 wt% levodopa, 65 wt% carbidopa, 10 wt% hydroxypropyl cellulose, and 1 wt% aspartame; or

[0128] When the outer coating consists of 54 wt% levodopa, 35 wt% carbidopa, 10 wt% hydroxypropyl cellulose, 0.9 wt% aspartame, and 0.1 wt% peppermint essence; or

[0129] When the outer coating consists of 42.8 wt% levodopa, 46.2 wt% carbidopa, 10 wt% hydroxypropyl cellulose, 0.9 wt% aspartame, and 0.1 wt% peppermint essence; or

[0130] 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% peppermint essence.

[0131] Further more preferably, the weight gain of the outer coating relative to the tablet core is 12.9% or 13.2% or 15.7% or 21.0% by weight percentage.

[0132] Preferably, the pharmaceutical composition consists of a drug-containing layer and a coating film. 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, where wt% is the weight percentage in the drug-containing layer; the coating film consists of 50 wt% cellulose acetate film and 50 wt% copovidone VA64, where wt% is the weight percentage in the coating film; the weight of the coating film is 2.0% of the weight of the tablet core. For the dosage form containing this pharmaceutical composition, an outlet hole with a diameter of 0.5 mm is mechanically drilled on the drug layer side of the coated tablet, and levodopa and carbidopa are delivered at average rates of 14.17 mg / hr and 4.59 mg / hr, respectively, and 85% of the drug is delivered in 12 hours and 10 hours, respectively. This dosage form can be held in the mouth until the osmotic layer reaches the delivery port, or held there for 8 - 9 hours and then swallowed.

[0133] The pharmaceutical composition consists of a drug-containing layer and a coating film. The drug-containing layer is composed of 38 wt% of levodopa, 50 wt% of microcrystalline cellulose, 10 wt% of hypromellose, and 2 wt% of magnesium stearate, where wt% is the weight percentage in the drug-containing layer; the coating film is composed of 50 wt% of cellulose acetate membrane and 50 wt% of copovidone VA64, where wt% is 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 with a 4.5% film weight gain delivers levodopa at an average rate of 9.4 mg / hr and delivers 85% of levodopa within 9.0 hours.

[0134] Alternatively, the pharmaceutical composition consists of a drug-containing layer and a coating film. The drug-containing layer is composed of 19.5 wt% of levodopa, 20 wt% of carbidopa, 50 wt% of mannitol, 10 wt% of citric acid, and 0.5 wt% of magnesium stearate, where wt% is the weight percentage in the drug-containing layer; the coating film is composed of 50 wt% of cellulose acetate membrane and 50 wt% of copovidone VA64, where wt% is 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 with a 4.5% film weight gain delivers levodopa at an average rate of 22.9 mg / hr and delivers 85% of levodopa within 13.0 hours.

[0135] Preferably, in one embodiment, the pharmaceutical composition comprises a drug-containing layer, an osmotic pusher layer and a coating film. The drug-containing layer consists 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, where wt% is the weight percentage in the drug-containing layer; the osmotic pusher layer consists of 55 wt% sodium carboxymethyl cellulose 7H4XF or 9H4XF, 5 wt% polyvinylpyrrolidone K30, 39 wt% sorbitol, 0.5 wt% iron oxide red and 0.5 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pusher layer; the coating film consists of 70 wt% cellulose acetate membrane and 30 wt% copolyvidone VA64, where wt% is the 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 carboxymethyl cellulose is 7H4XF, the dosage form containing the pharmaceutical composition with an outlet hole of 0.5 mm on the drug layer side and a coating film weight of 5.0% of the tablet core weight delivers levodopa and carbidopa at average rates of 17.0 mg / hr and 4.6 mg / hr, respectively, and delivers 85% of the drug within 10.0 hours. The dosage form can be held in the mouth until the osmotic layer reaches the delivery port, or held in the mouth for 6 - 7 hours and then swallowed. When the orifice size of the delivery port changes to 0.5 mm, 0.75 mm and 1.0 mm, the dosage form with a coating film weight of 4.0% of the tablet core weight delivers levodopa and carbidopa at average rates of 21.3 mg / hr and 5.7 mg / hr, respectively, and delivers 85% of the drug within 8.0 hours. The dosage form can be held in the mouth until the osmotic layer reaches the delivery port, or held in the mouth for 4 - 5 hours and then swallowed. When the sodium carboxymethyl cellulose is 9H4XF, the dosage form with a 2.0% increase in the coating film weight delivers levodopa and carbidopa at average rates of 24.3 mg / hr and 6.6 mg / hr, respectively, and delivers 85% of the drug within 7.0 hours. The dosage form can be held in the mouth until the osmotic layer reaches the delivery port, or held in the mouth for 3 - 4 hours and then swallowed.

[0136] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pusher layer, and a coating film. The drug-containing layer consists 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, where wt% is the weight percentage in the drug-containing layer; the osmotic pusher layer consists of 55 wt% sodium carboxymethyl cellulose 7H4XF, 5 wt% povidone K30, 39 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pusher layer; the coating film consists of 60 wt% cellulose acetate membrane and 40 wt% copovidone VA64, where wt% is the 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 this pharmaceutical composition delivered 85% of the drug within 6 hours. The dosage form can be held in the mouth until the osmotic layer reaches the delivery orifice, or held there for 2 - 3 hours and then swallowed.

[0137] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pusher layer, and a coating film. The drug-containing layer consists of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 16 wt% mannitol, 5% povidone K30, 1 wt% magnesium stearate, 1 wt% peppermint essence, and 1 wt% aspartame, where wt% is the weight percentage in the drug-containing layer; the osmotic pusher layer consists of 55 wt% sodium carboxymethyl cellulose 7H4XF, 10 wt% povidone K30, 34 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pusher layer; the coating film consists of 60 wt% cellulose acetate membrane and 40 wt% copovidone VA64, where wt% is the 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. The dosage forms containing this pharmaceutical composition and having 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, and delivered 85% of levodopa within 5.0 hours, 7.0 hours, and 9.0 hours, respectively.

[0138] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pushing layer, and a coating film. The drug-containing layer consists of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 16 wt% mannitol, 5% polyvinylpyrrolidone K30, 1 wt% magnesium stearate, 1% peppermint essence, and 1% aspartame, where wt% is the weight percentage in the drug-containing layer; the osmotic pushing layer consists of 55 wt% sodium carboxymethyl cellulose 7H4XF, 10 wt% polyvinylpyrrolidone K30, 34 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pushing layer; the coating film consists of 70 wt% cellulose acetate membrane and 30 wt% copolyvidone VA64, where wt% is the 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 this pharmaceutical composition with film weight increases of 4.6% and 7.9% deliver levodopa at average rates of 25.5 mg / hr and 16.9 mg / hr, respectively, and deliver 85% of levodopa in 7.5 hours and 11.5 hours, respectively.

[0139] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pushing layer, and a coating film. The drug-containing layer consists of 70 wt% levodopa, 9 wt% mannitol, 20 wt% polyvinylpyrrolidone K30, and 1 wt% magnesium stearate, where wt% is the weight percentage in the drug-containing layer; the osmotic pushing layer consists of 85 wt% sodium carboxymethyl cellulose, 3 wt% polyvinylpyrrolidone K30, 5 wt% sorbitol, 5 wt% iron oxide red, and 2 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pushing layer; the coating film consists of 70 wt% cellulose acetate membrane and 30 wt% copolyvidone VA64, where wt% is the weight percentage in the coating film; the weight of the coating film is 4.5% of the weight of the tablet core. Dosage forms containing this pharmaceutical composition deliver levodopa at an average rate of 35.0 mg / hr and deliver 85% of levodopa within 8.5 hours.

[0140] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pusher layer, and a coating film. 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, where wt% is the weight percentage in the drug-containing layer; the osmotic pusher layer consists of 25 wt% sodium carboxymethyl cellulose, 9.5 wt% polyvinylpyrrolidone K30, 65 wt% sorbitol, and 0.5 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pusher layer; the coating film consists of 90 wt% cellulose acetate membrane and 10 wt% copolyvidone VA64, where wt% is 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 this pharmaceutical composition delivers levodopa and carbidopa at an average rate of 7.1 mg / hr and delivers 85% of levodopa / carbidopa within 12 hours.

[0141] Preferably, in one embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pusher layer, a coating film, and an outer coating. The drug-containing layer consists of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 16 wt% mannitol, 5% polyvinylpyrrolidone K30, 1 wt% magnesium stearate, 1 wt% peppermint essence, and 1 wt% aspartame, where wt% is the weight percentage in the drug-containing layer; the osmotic pusher layer consists of 55 wt% sodium carboxymethyl cellulose 7H4XF, 10 wt% polyvinylpyrrolidone K30, 34 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pusher layer; the coating film consists of 70 wt% cellulose acetate membrane and 30 wt% copolyvidone VA64, where wt% is the weight percentage in the coating film, and the weight of the coating film is 4.8% or 7.7% of the weight of the tablet core; the outer coating contains an immediate-release composition of 23.78 wt% levodopa, 64.22 wt% carbidopa, 10 wt% hydroxypropyl cellulose, 1 wt% aspartame, and 1 wt% peppermint essence, where wt% is the weight percentage in the outer coating, and the outer coating increases the weight of the tablet core by 13.2% and 12.9% respectively by weight percentage. The release curve of the dosage form containing this pharmaceutical composition shows a rapid release of levodopa / carbidopa, and the sustained-release durations of the dosage forms with coating film weight increases of 4.8% and 7.7% are approximately 8.5 hours and 12.0 hours respectively. The dosage form with a 4.8% increase in film weight can remain in the mouth for 4 - 5 hours and then remain in the mouth during feeding time or throughout the release period. The dosage form with a 7.7% increase in film weight can remain in the mouth for 8 - 9 hours before swallowing or throughout the release period.

[0142] In another embodiment, the pharmaceutical composition is composed of a drug-containing layer, an osmotic pusher layer, a coating film, and an outer coating. The drug-containing layer is composed of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 17 wt% mannitol, 5 wt% polyvinylpyrrolidone K30, 1 wt% magnesium stearate, and 1 wt% aspartame, where wt% is the weight percentage in the drug-containing layer; the osmotic pusher layer is composed of 60 wt% sodium carboxymethyl cellulose 7H4XF, 10 wt% polyvinylpyrrolidone K30, 26 wt% sorbitol, 2 wt% iron oxide red, and 2 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pusher layer; the coating film is composed of 70 wt% cellulose acetate membrane and 30 wt% copolyvinylpyrrolidone VA64, where wt% is the weight percentage in the coating film, and the weight of the coating film is 4.8% of the weight of the tablet core; the outer coating contains a rapid-release composition of 93 wt% CD, 2 wt% hydroxypropyl cellulose, and 5 wt% aspartame, where wt% is the weight percentage in the outer coating, and the weight gain of the outer coating relative to the tablet core is 13.2% by weight percentage. The rapid-release outer coating of the dosage form is released rapidly first, and then the release duration is about 8 hours of sustained release. The dosage form can be held in the mouth for 4 - 5 hours, and then swallowed before eating or held in the mouth during the entire release period.

[0143] In another embodiment, the pharmaceutical composition is composed of a drug-containing layer, an osmotic pusher layer, a coating film, and an outer coating. The drug-containing layer is composed of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 12 wt% mannitol, 5 wt% polyvinylpyrrolidone K30, 5 wt% mint essence, 1 wt% aspartame, and 1 wt% magnesium stearate, where wt% is the weight percentage in the drug-containing layer; the osmotic pusher layer is composed of 40 wt% sodium carboxymethyl cellulose 7H4XF, 20 wt% polyvinylpyrrolidone K30, 36 wt% sorbitol, 3.5 wt% iron oxide red, and 0.5 wt% magnesium stearate, where wt% is the weight percentage in the osmotic pusher layer; the coating film is composed of 70 wt% cellulose acetate membrane and 30 wt% copolyvinylpyrrolidone VA64, where wt% is the weight percentage in the coating film, and the weight of the coating film is 4.8% of the weight of the tablet core; the outer coating contains a rapid-release composition of 75 wt% levodopa, 20 wt% hydroxypropyl cellulose, and 5 wt% mint essence, where wt% is the weight percentage in the outer coating, and the weight gain of the outer coating relative to the tablet core is 13.2% by weight percentage. The rapid-release outer coating of the dosage form is released rapidly first, and then the release duration is about 8 hours of sustained release. The dosage form can be held in the mouth for 4 - 5 hours, and then swallowed before eating or held in the mouth during the entire release period.

[0144] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pusher layer, a coating film, and an outer coating. The drug-containing layer is composed of 62.5 wt% of levodopa, 31 wt% of hydroxypropyl cellulose, 4.5 wt% of mannitol, 0.1 wt% of peppermint essence, 0.9 wt% of aspartame, and 1 wt% of magnesium stearate, where wt% is the weight percentage of each component in the drug-containing layer; the osmotic pusher layer is composed of 55 wt% of sodium carboxymethyl cellulose 7H4XF, 10 wt% of hydroxypropyl cellulose, 34 wt% of sorbitol, 0.5 wt% of iron oxide red, and 0.5 wt% of magnesium stearate, where wt% is the weight percentage of each component in the osmotic pusher layer; the coating film is composed of 70 wt% of cellulose acetate membrane and 30 wt% of copovidone VA64, where wt% 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 an immediate-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 peppermint essence, where wt% is the weight percentage of each component in the outer coating, and the outer coating has a weight gain of 21.0% relative to the tablet core by weight percentage.

[0145] In another embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pusher layer, a coating film, and an outer coating. The drug-containing layer is composed of 46.9 wt% of levodopa, 31 wt% of hydroxypropyl cellulose, 20.1 wt% of mannitol, 0.1 wt% of peppermint essence, 0.9 wt% of aspartame, and 1 wt% of magnesium stearate, where wt% is the weight percentage of each component in the drug-containing layer; the osmotic pusher layer is composed of 55 wt% of sodium carboxymethyl cellulose 7H4XF, 10 wt% of hydroxypropyl cellulose, 34 wt% of sorbitol, 0.5 wt% of iron oxide red, and 0.5 wt% of magnesium stearate, where wt% is the weight percentage of each component in the osmotic pusher layer; the coating film is composed of 70 wt% of cellulose acetate membrane and 30 wt% of copovidone VA64, where wt% 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 an immediate-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 peppermint essence, where wt% is the weight percentage of each component in the outer coating, and the outer coating has a weight gain of 15.7% relative to the tablet core by weight percentage.

[0146] In a specific preferred embodiment, the pharmaceutical composition is composed of a drug-containing layer, an osmotic pushing layer, a coating film, and an outer coating; wherein, the drug-containing layer is composed of 45 wt% of levodopa, 31 wt% of hydroxypropyl cellulose, 16 wt% of mannitol, 5 wt% of polyvinylpyrrolidone K30, 1 wt% of magnesium stearate, 1 wt% of peppermint essence, and 1 wt% of aspartame, and wt% is the weight percentage of each component in the drug-containing layer; the osmotic pushing layer is composed of 55 wt% of sodium carboxymethyl cellulose 7H4XF, 10 wt% of hydroxypropyl cellulose, 34 wt% of sorbitol, 0.5 wt% of iron oxide red, and 0.5 wt% of magnesium stearate, and wt% is the weight percentage of each component in the osmotic pushing layer; the coating film is composed of 70 wt% of cellulose acetate and 30 wt% of copovidone V64, and wt% is the weight percentage of each component in the coating film; wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of 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 64.22 wt% of levodopa, 23.78 wt% of carbidopa, 10 wt% of hydroxypropyl cellulose, 1 wt% of aspartame, and 1% of peppermint essence, and 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 the 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 obtained dosage form is 1.7 ppm, and the content of the carbidopa-related impurity dihydroxyphenylacetone (DHPA) is 0.21%. When the coating solution solvent of the outer coating is purified water, the solid suspension concentration of the outer coating is 10.0 wt%, including 24.0 wt% of levodopa, 65.0 wt% of carbidopa monohydrate, 10.0 wt% of hydroxypropyl cellulose, and 1.0 wt% of aspartame, by weight percentage; the content of the carbidopa-related genotoxic impurity hydrazine in the obtained dosage form is 3.8 ppm, and the content of the carbidopa-related impurity DHPA is 0.28%. When the coating solution solvent of the outer coating is anhydrous ethanol, the carbidopa-related genotoxic impurity hydrazine and the impurity DHPA in the obtained dosage form are significantly lower than those in the dosage form obtained when the coating solution solvent of the outer coating is purified water. The immediate-release outer coating of the dosage form is first rapidly released, and then continuously released at a constant rate for about 8 hours. The osmotic delivery system can be retained in the oral cavity for 3 - 5 hours, and then swallowed before eating or retained in the oral cavity during the entire release period.

[0147] In a specific preferred embodiment, the pharmaceutical composition is composed of a drug-containing layer, an osmotic pushing layer, a coating film and an outer coating; the drug-containing layer is composed of 45 wt% of levodopa, 31 wt% of hydroxypropyl cellulose, 22 wt% of mannitol, 0.9 wt% of aspartame, 0.5 wt% of magnesium stearate and 0.1 wt% of peppermint essence, where wt% is the weight percentage of each component in the drug-containing layer; the osmotic pushing layer is composed of 55 wt% of sodium carboxymethyl cellulose 7H4XF, 10 wt% of hydroxypropyl cellulose, 34 wt% of sorbitol, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate, where wt% is the weight percentage of each component in the osmotic pushing layer; the coating film is composed of 70 wt% of cellulose acetate and 30 wt% of 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 39.8 wt% of 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 54 wt% of levodopa, 35 wt% of carbidopa, 10 wt% of hydroxypropyl cellulose, 0.9 wt% of aspartame and 0.1 wt% of peppermint essence, 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 the coating film. The final dosage form contains an immediate-release coating layer of 62.5 mg of levodopa and 37.5 mg of carbidopa, and 187.5 mg of levodopa is contained in the controlled-release drug layer. The immediate-release outer coating of the dosage form is released rapidly first, and then the release continues for about 8 hours in a sustained-release manner. The osmotic delivery system can remain in the oral cavity for 4 - 5 hours, and then be swallowed before eating or remain in the oral cavity throughout the release period.

[0148] In a specific preferred embodiment, the pharmaceutical composition is composed of a drug-containing layer, an osmotic pushing layer, a coating film and an outer coating; the drug-containing layer is composed of 45 wt% of levodopa, 31 wt% of hydroxypropyl cellulose, 22 wt% of mannitol, 0.9 wt% of aspartame, 0.5 wt% of magnesium stearate and 0.1 wt% of peppermint essence, where wt% is the weight percentage of each component in the drug-containing layer; the osmotic pushing layer is composed of 55 wt% of sodium carboxymethyl cellulose 7H4XF, 10 wt% of hydroxypropyl cellulose, 34 wt% of sorbitol, 0.5 wt% of iron oxide red and 0.5 wt% of magnesium stearate, where wt% is the weight percentage of each component in the osmotic pushing layer; the coating film is composed of 70 wt% of cellulose acetate and 30 wt% of 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 39.8 wt% of acetyl groups, and the weight of the coating film is 7.0% of the weight of the tablet core; and, the outer coating is composed of 42.8 wt% of levodopa, 46.2 wt% of carbidopa, 10 wt% of hydroxypropyl cellulose, 0.9 wt% of aspartame and 0.1 wt% of peppermint essence, 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 the coating film. The final dosage form contains an immediate-release coating layer of 37.5 mg of levodopa and 37.5 mg of carbidopa, and 112.5 mg of levodopa is contained in the controlled-release drug layer. The immediate-release outer coating of the dosage form is released rapidly first, and then the release duration is about 8 hours of sustained release. The osmotic delivery system can be retained in the oral cavity for 4-5 hours, and then swallowed before eating or retained in the oral cavity during the entire release period.

[0149] In a specific preferred embodiment, the pharmaceutical composition consists of a drug-containing layer, an osmotic pushing layer, a coating film, and an outer coating; the drug-containing layer consists of 45 wt% levodopa, 31 wt% hydroxypropyl cellulose, 22 wt% mannitol, 0.9 wt% aspartame, 1 wt% magnesium stearate, and 0.1 wt% peppermint essence, where wt% is the weight percentage of each component in the drug-containing layer; the osmotic pushing layer consists of 55 wt% sodium carboxymethyl cellulose 7H4XF, 10 wt% hydroxypropyl cellulose, 34 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate, where wt% is the weight percentage of each component in the osmotic pushing layer; the coating film consists of 70 wt% cellulose acetate and 30 wt% 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 39.8 wt% acetyl groups, and the weight of the coating film is 9.0% of the weight of the tablet core; and, 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% peppermint essence, 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 the coating film. The final dosage form contains an immediate-release coating layer of 18.75 mg levodopa and 37.5 mg carbidopa, and 56.25 mg levodopa is contained in the controlled-release drug layer. The immediate-release outer coating of the dosage form is released rapidly first, and then the release continues for about 8 hours in a sustained-release manner. The osmotic delivery system can be retained in the oral cavity for 4 - 5 hours, and then swallowed before eating or retained in the oral cavity throughout the release period.

[0150] Among them, the preparation method of the above outer coating includes: dissolving each component of the outer coating in the above weight percentage in absolute ethanol to form a coating solution, preferably the ratio of each component of the outer coating to absolute ethanol is 1:10. In this pharmaceutical composition, carbidopa only exists in the immediate-release outer coating, and the sustained-release tablet core part does not contain carbidopa. This dosage form has the following advantages: the contents of carbidopa-related genotoxic impurities hydrazine and impurity dihydroxyphenylacetone (DHPA) are lower. When the solvent of the coating solution of the outer coating is absolute ethanol, the contents of carbidopa-related genotoxic impurities hydrazine and impurity DHPA in the obtained dosage form are significantly lower than those in the dosage form obtained when the solvent of the coating solution of the outer coating is pure water.

[0151] Unless otherwise specified, the preparation method of the above pharmaceutical composition is a conventional preparation method in the art.

[0152] 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 is a capsule-shaped tablet 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 contains 62.5 mg of CD and 375 mg of LD, or contains 62.5 mg of carbidopa and 250 mg of levodopa, or contains 50 mg of carbidopa and 500 mg of levodopa, or contains 37.5 mg of carbidopa and 375 mg of levodopa.

[0153] To solve the above technical problems, one of the technical solutions of the present invention is: a method for using the above controlled release dosage form, that is, placing the controlled release platform in the personalized customized retention platform, and fixing the retention platform on the corresponding teeth in the oral cavity; after 4-24 hours, take out the controlled release dosage form, replace the new controlled release platform, and refix the retention platform on the corresponding teeth in the oral cavity to enable continuous and stable drug release.

[0154] To solve the problem that in the prior art, after some patients wear the drug delivery device and perform actions such as opening the mouth wide, the drug delivery device has a risk of falling off, another technical solution of the present disclosure is: an oral drug delivery device, which includes a core component and a fixing device, and the core component includes an integrally formed molar fitting function area and a drug loading function area;

[0155] When the oral drug delivery device is fixed in the oral cavity, the drug loading function area is located in the space between the teeth and the cheek, or the drug loading function area is located in the space between the teeth and the tongue;

[0156] The molar fitting function area includes a first section close to the drug loading function area and a second section far from the drug loading function area; one ends of the first section and the second section are connected to each other, and the other ends are open ends, forming a U-shaped structure; the first section and the second section are respectively used to fit with the buccal side and the lingual side of the teeth to fix the drug loading function area on the teeth;

[0157] The drug loading function 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;

[0158] 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;

[0159] When the fixing device is a fixator:

[0160] When the oral drug delivery device is in use, the lingual side, buccal side and occlusal surface of the retainer correspondingly fit with the lingual side, buccal side and occlusal surface of the tooth and wrap around the outer peripheral surface of the tooth; the retainer simultaneously wraps around the molar anastomosis functional area;

[0161] When the fixing device is a fixing layer:

[0162] The fixing layer is attached to the outer surfaces of the first section and the second section that are used to contact the teeth.

[0163] In the present disclosure, the oral drug delivery device is similar to the above-mentioned oral retention device.

[0164] In the present disclosure, the first ring and the second ring are preferably located on the buccal side of the first or second molar.

[0165] In the present disclosure, the retainer is preferably connected to the molar anastomosis functional area by mechanical assembly, mechanical connection or adhesive bonding.

[0166] Among them, the mechanical assembly is preferably embedding. A slot is provided at the position of the retainer corresponding to the drug-loading functional area to achieve detachable fixation of the retainer and the core component. The meaning of embedding is that the molar anastomosis functional area is embedded into the space formed on both sides of the retainer.

[0167] Among them, the mechanical connection is preferably welding, riveting or bolting.

[0168] Among them, the adhesive is preferably one or more of pressure-sensitive adhesive, starch adhesive, latex, epoxy resin and polyurethane acrylate.

[0169] In the present disclosure, the fixing layer is preferably also attached to the other outer surfaces of the first section and the second section.

[0170] In the present disclosure, the first ring is close to the open end of the molar anastomosis functional area, the second ring is far from the open end of the molar anastomosis functional area, and the first ring and the second ring are preferably solid or hollow ring-shaped structures.

[0171] Among them, the hollow ring-shaped structure is a closed loop or an open loop.

[0172] Among them, the shape of the ring-shaped structure is preferably one or more of circular, elliptical and polygonal.

[0173] Among them, the shapes of the ring-shaped structures of the first ring and the second ring are preferably both 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.

[0174] 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 noble metal, more preferably cobalt-chromium alloy, and the material of the core component meets the standards of dental use materials.

[0175] In the present disclosure, the material of the retainer is preferably one or more of polyvinyl chloride, polyethylene terephthalate, polyethylene terephthalate-1,4-cyclohexanedimethanol ester, polyurethane, polyamide, ethylene-vinyl acetate copolymer, polycaprolactone, high-density polyethylene, polypropylene, epoxy acrylate, methacrylate, polyurethane acrylate; more preferably polyethylene terephthalate or ethylene-vinyl acetate copolymer, and the material of the retainer meets the medical grade standards.

[0176] 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 ester, 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 material of the fixing layer meets the medical grade standards.

[0177] In the present disclosure, the thickness of the fixing layer is preferably 0.01 mm - 1 mm.

[0178] In the present disclosure, the number of teeth covered by the retainer can be adjusted according to the tooth condition and wearing firmness. The length of the retainer is preferably the length corresponding to 4 - 16 teeth in the upper or lower jaw, more preferably the length corresponding to 5 - 9 teeth in the upper or lower jaw.

[0179] In the present disclosure, the length of the molar anastomosis functional area is preferably the length corresponding to 2 - 5 teeth in the lower jaw.

[0180] Among them, those skilled in the art should understand that the length is such that the retainer or the molar anastomosis functional area can cover the number of teeth, and will not exceed the number of teeth in the target range.

[0181] In a preferred embodiment, the retainer and the molar anastomosis functional area are connected in an embedded manner. A slot is provided at the position of the retainer corresponding to the drug-loading functional area to achieve detachable fixation of the retainer and the core component; the length of the molar anastomosis functional area is the length corresponding to the first and second premolars and the first and second molars in the lower jaw; the first ring and the second ring are circular closed loops.

[0182] In a preferred embodiment, the fixator is connected to the molar anastomosis functional area in an embedded manner; the length of the molar anastomosis functional area corresponds to the lengths of the first and second mandibular premolars and the first and second molars; the first ring and the second ring are oval closed loops.

[0183] In a preferred embodiment, the fixator is connected to the molar anastomosis functional area in an embedded manner; the length of the molar anastomosis functional area corresponds to the lengths of the second maxillary premolar and the first, second, and third molars, and the first ring and the second ring are circular closed loops.

[0184] In a preferred embodiment, the fixator is connected to the molar anastomosis functional area by an adhesive bonding method using pressure-sensitive adhesive; the length of the molar anastomosis functional area corresponds to the lengths of the first, second, and third molars; the first ring and the second ring are polygonal closed loops.

[0185] In a preferred embodiment, the fixing layer is disposed on the entire outer surfaces of the first section and the second section of the U-shaped structure; the length of the molar anastomosis functional area corresponds to the lengths of the first and second mandibular premolars and the first and second molars; the first ring and the second ring are circular closed loops.

[0186] 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 anastomosis functional area.

[0187] Another technical solution of the present disclosure is: a preparation method of the above oral medicator, which includes the following steps: when the fixing device is a fixator, combining the fixator with the integrally formed first section and second section in a covering form; when the fixing device is a fixing layer, disposing the fixing layer on the outer surfaces of the integrally formed first section and second section.

[0188] In the present disclosure, the preparation method of the core component preferably includes laser melting casting, injection molding, or impression molding.

[0189] Among them, the step of laser melting casting is preferably: scanning the subject's oral cavity or scanning after taking an oral mold to make a plaster model to obtain the subject's oral cavity data; using three-dimensional design software and dental design software to respectively design the drug-loading functional area and the 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 through laser melting casting, grinding, polishing, and cleaning.

[0190] Among them, the step of injection molding is preferably: taking an oral mold of the subject and making a plaster model; using dental wax as the material to prepare a dental wax model on the plaster model, and preparing the core component through traditional injection molding process.

[0191] In the present disclosure, the preparation method of the retainer preferably includes thermoforming, impression taking, cutting or 3D printing.

[0192] Among them, the step of thermoforming is preferably: heating and softening the raw material of the retainer through a thermoforming machine and then evacuating, so that the raw material of the retainer covers the dental mold and the masticatory anastomosis functional area.

[0193] Among them, the step of impression taking is preferably: heating and softening the raw material of the retainer, and covering it on the teeth of the subject and the masticatory anastomosis functional area.

[0194] In the present disclosure, the raw material of the retainer is preferably as described above.

[0195] In the present disclosure, the preparation method of the fixing layer preferably includes dip coating, spraying or thermoforming.

[0196] Among them, the step of dip coating is preferably: dissolving the raw material of the fixing layer, immersing the masticatory anastomosis functional area into the raw material solution of the fixing layer, taking it out, and drying to form a film.

[0197] Among them, the step of spraying is preferably: dissolving the raw material of the fixing layer and then coating it on the masticatory anastomosis functional area by spraying, and drying to form a film.

[0198] Among them, the step of thermoforming is preferably: heating and softening the raw material of the fixing layer, covering the masticatory anastomosis functional area, and then cooling.

[0199] In the present disclosure, the raw material of the fixing layer is preferably as described above.

[0200] In the present disclosure, the formation method of the coating structure of the retainer and the first section and the second section is preferably mechanical assembly, mechanical connection or adhesive bonding.

[0201] Among them, the form of mechanical assembly is preferably embedding.

[0202] When the combination method is mechanical assembly, the retainer fits with the dental mold and the core component during the forming process, and a structure similar to a card slot is naturally formed. At the same time, a buckle design can be added to the masticatory anastomosis functional area as needed.

[0203] Among them, the form of mechanical connection is preferably welding, riveting or bolting.

[0204] Among them, the coating position of the adhesive is preferably the outer surface for contacting the teeth in the first section and the second section, and more preferably the entire outer surface of the first section and the second section.

[0205] Among them, the coating thickness of the adhesive is preferably not more than 1.0 mm.

[0206] Another technical solution of the present disclosure is: an application of the above oral medicator, characterized in that: when the fixing device is a retainer: the lingual side, buccal side and occlusal surface of the retainer are correspondingly mated with the lingual side, buccal side and occlusal surface of the tooth and wrapped around the outer peripheral surface of the tooth; the drug-carrying functional area is placed in the space between the tooth and the cheek, or the drug-carrying functional area is placed in the space between the tooth and the tongue; and the retainer wraps the molar mating functional area;

[0207] When the fixing device is a fixing layer: the drug-carrying functional area is placed in the space between the tooth and the cheek, or the drug-carrying functional area is placed in the space between the tooth and the tongue.

[0208] Another technical solution of the present disclosure is: a controlled release platform, as described above.

[0209] As described above, the controlled release platform or the pharmaceutical composition of the present invention can also be called an osmotic pump tablet. The osmotic pump tablet of the present disclosure can be used in combination with the aforementioned oral retention device or oral medicator.

[0210] The present disclosure further relates to an osmotic pump tablet, which includes 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. 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.

[0211] In some embodiments, 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%.

[0212] In some embodiments, the hydroxypropyl cellulose is preferably hydroxypropyl cellulose with a weight average molecular weight of about 80,000. The Brookfield viscosity of the hydroxypropyl cellulose is about 300 - 600 mPa·s. The concentration is about 10%.

[0213] In some embodiments, the hydroxypropyl cellulose is hydroxypropyl cellulose EXF.

[0214] In some embodiments, the hydrophilic polymer may further include conventional hydrophilic polymers in the art, such as one or more of hydroxypropyl methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone and hydroxyethylcellulose. That is, the hydrophilic polymer is a mixture of hydroxypropyl cellulose and one or more selected from hydroxypropyl methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone and hydroxyethylcellulose.

[0215] In some embodiments, 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 further for example, 5 wt% - 10 wt%.

[0216] In some embodiments, the poloxamer is poloxamer 407 (P407).

[0217] In some embodiments, the surfactant may further include surfactants conventional in the art, such as one or more of polysorbate, fatty acid glyceride, sodium dodecylbenzenesulfonate, and sodium dodecyl sulfate. That is, the surfactant is a mixture of poloxamer and one or more selected from polysorbate, fatty acid glyceride, sodium dodecylbenzenesulfonate, and sodium dodecyl sulfate.

[0218] In some embodiments, 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 further for example, 58 wt% - 63 wt%.

[0219] In some embodiments, the drug active ingredient is a drug active ingredient that is released in the oral cavity.

[0220] In some embodiments, the drug active ingredient is a drug for oral local treatment or absorption at the upper digestive tract.

[0221] In some embodiments, the drug active ingredient is selected from one or more of levodopa or its esters or salts, carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin; preferably selected from one or two of levodopa or its esters and carbidopa. Among them, the ester of levodopa can be an alkyl ester of levodopa or a deuterated alkyl ester of levodopa, such as methyl levodopa hydrochloride. The salt of levodopa is, for example, ethyl levodopa hydrochloride.

[0222] In some other embodiments, the drug active ingredient is, for example, selected from antifungal drugs and anti-tumor drugs. Among them, the antifungal drugs are, for example, selected from one or more of nystatin, fluconazole, posaconazole, isavuconazole, voriconazole, anidulafungin, caspofungin, and micafungin. The anti-tumor drugs are, for example, selected from one or more of 5-fluorouracil, paclitaxel, and capecitabine.

[0223] In some embodiments, the drug-containing layer further includes other excipients, and the other excipients are selected from one or more of permeants, drug carriers, binders, lubricants, antioxidants, and flavoring agents.

[0224] In some embodiments, 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; for example, it is 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, for example 5 - 20 wt%, and for example 10.0 wt%, 14.87 wt%, 15.0 wt%, and 19.87 wt%.

[0225] In some embodiments, 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%, and for example 5 - 50 wt%, and for example 5 - 10 wt%.

[0226] In some embodiments, the binder is selected from one or more of methylcellulose, 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%, and for example 5 - 50 wt%, and for example 5 - 10 wt%.

[0227] In some embodiments, povidone can act as both a hydrophilic polymer, a drug carrier, and a binder.

[0228] In some embodiments, hydroxypropyl cellulose can act as both a hydrophilic polymer and a binder.

[0229] In some embodiments, 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; for example, 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, for example 0.5 - 2.5 wt%, and for example 1 - 2 wt%.

[0230] In some embodiments, the antioxidant can be one or more of dibutylhydroxytoluene, butylated hydroxyanisole, tert-butylhydroquinone, propyl gallate, vitamin C, and vitamin E; for example, dibutylhydroxytoluene. Preferably, based on the total weight of the drug-containing layer, the content of the antioxidant is 0 - 1 wt%, but not 0; for example, 0.01 - 0.1 wt%.

[0231] In some embodiments, the flavoring agent is 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. Preferably, based on the total weight of the drug-containing layer, the content of the flavoring agent is 0-10 wt%, such as 0-2 wt%, but not 0; for example, it is 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%.

[0232] 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.

[0233] In some embodiments, the drug-containing layer comprises any one of the following combinations:

[0234] (1) 50 wt%-75 wt% of a pharmaceutically active ingredient, 5-25 wt% of a hydrophilic polymer, 1-15 wt% of a surfactant, 0.5-50 wt% of a binder, 5-20 wt% of a penetrant, 0.5-3 wt% of a lubricant and 1-10 wt% of a flavoring agent;

[0235] (2) 50 wt%-75 wt% of a pharmaceutically active ingredient, 5-25 wt% of a hydrophilic polymer, 1-15 wt% of a surfactant, 0.5-50 wt% of a binder, 5-20 wt% of a penetrant, 0.5-3 wt% of a lubricant, 0.01-1 wt% of an antioxidant and 1-10 wt% of a flavoring agent;

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

[0237] (4) 50 wt%-75 wt% of a pharmaceutically active ingredient, 5-25 wt% of a hydrophilic polymer, 1-15 wt% of a surfactant, 0.5-50 wt% of a binder, 5-20 wt% of a penetrant and 0.5-3 wt% of a lubricant.

[0238] In some embodiments, the drug-containing layer comprises 63.0 wt% of levodopa, 10.0 wt% of hydroxypropyl cellulose (EXF, with a 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 essence, and 1.0 wt% of magnesium stearate.

[0239] In some embodiments, the drug-containing layer comprises 58.0 wt% of levodopa, 15.0 wt% of hydroxypropyl cellulose (EXF, with a 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 essence, 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 hydroxypropyl cellulose (EXF, 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, 0.1 wt% of mint essence, and 1.0 wt% of magnesium stearate.

[0241] In some embodiments, the drug-containing layer comprises 54.9 wt% of levodopa, 3.16 wt% of carbidopa, 15.0 wt% of hydroxypropyl cellulose (EXF, with a 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 essence, 0.1 wt% of dibutylhydroxytoluene, 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 hydroxypropyl cellulose (EXF, with a 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 essence, 0.1 wt% of dibutylhydroxytoluene, and 1.0 wt% of magnesium stearate.

[0243] In some embodiments, the drug-containing layer comprises 63.0 wt% of levodopa, 11.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32), 10.0 wt% of sorbitol, 10.0 wt% of poloxamer (P407), and 1.00 wt% of magnesium stearate.

[0244] In some embodiments, the drug-containing layer comprises 63.0 wt% of levodopa, 11.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (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.

[0245] In some embodiments, the tablet core 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. The coating film is wrapped outside the tablet core. In the present disclosure, the boosting layer and the osmotic pushing layer as described above have the same meaning and can be replaced with each other.

[0246] In some embodiments, the mass ratio of the drug-containing layer to the boosting layer is about 0.5:1 - 4:1, such as 1.5:1 - 3.5:1.

[0247] In some embodiments, the boosting 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.

[0248] In some embodiments, 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%, such as 49.0 - 68.5 wt%.

[0249] In some embodiments, 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%, such as 10.0 - 30.0 wt%.

[0250] 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, based on the total mass of the boosting layer, the content of the binder is 3-25 wt%, such as 20 wt%.

[0251] In some embodiments, 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, such as 0-3 wt%, or 0.5 wt%-1 wt%.

[0252] In some embodiments, 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, such as 0.5 wt%.

[0253] In some embodiments, the boosting layer comprises a swelling agent, a penetrant, a binder, a lubricant, and a colorant.

[0254] In some embodiments, the boosting layer comprises 49.0 wt% sodium carboxymethylcellulose (7H4XF), 30.0 wt% sorbitol, 20.0 wt% hydroxypropylcellulose (EXF), 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate.

[0255] In some embodiments, the boosting layer comprises 68.5 wt% sodium carboxymethylcellulose (7H4XF), 10.0 wt% sorbitol, 20.0 wt% hydroxypropylcellulose (EXF), 0.5 wt% iron oxide red, 0.5 wt% colloidal silica, and 0.5 wt% magnesium stearate.

[0256] In some embodiments, the boosting layer comprises 55.0 wt% sodium carboxymethylcellulose (7H4XF), 34.0 wt% sorbitol, 10.0 wt% hydroxypropylcellulose (EXF), 0.50 wt% iron oxide red, and 0.50 wt% magnesium stearate.

[0257] In some embodiments, the osmotic pump tablet further comprises 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. The coating film is wrapped outside the tablet core. Preferably, the barrier layer comprises one or more of ethylcellulose, cellulose acetate, acrylic resin and microcrystalline cellulose, such as ethylcellulose. Preferably, the mass ratio of the drug-containing layer to the barrier layer is (0.01-0.15):1, such as 0.05:1-0.1:1.

[0258] 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, ethylcellulose 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%.

[0259] In some embodiments, the coating film further comprises a plasticizer. The plasticizer can be a conventional plasticizer in the pharmaceutical field, such as 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.

[0260] 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.

[0261] In some embodiments, the tensile strength of the coating film is 1-10 Mpa.

[0262] In some embodiments, the elongation at break of the coating film is 1.1-2.0.

[0263] In some embodiments, the average thickness of the coating film is 100±8 μm to 200±10 μm.

[0264] In some embodiments, the aperture of the drug release hole can be 0.3 mm-1.2 mm.

[0265] In some embodiments, based on the total weight of the osmotic pump tablet, 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%.

[0266] In some embodiments, an immediate-release drug-containing outer coating may further be included outside the osmotic pump tablet. The immediate-release drug-containing outer coating includes a drug active ingredient and a pharmaceutical excipient. The drug active ingredient includes 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.

[0267] The drug active ingredient preferably includes levodopa, carbidopa, and a combination of the two. The pharmaceutical excipient preferably includes one or more of a binder, an antioxidant, and a plasticizer, and is preferably a binder.

[0268] The binder, antioxidant, and flavoring agent are all as described above (for example, those mentioned in the drug-containing layer of the osmotic pump tablet). The plasticizer is all as described above (for example, those mentioned in the coating film of the osmotic tablet). Herein, the binder is preferably hydroxypropyl cellulose (EXF). The antioxidant is preferably dibutylhydroxytoluene. The plasticizer is preferably triethyl citrate. The flavoring agent is preferably one or both of aspartame and mint essence.

[0269] In some embodiments, the content of the drug active ingredient is preferably 70 - 90 wt%, such as 77.3 - 77.5 wt%.

[0270] In some embodiments, the content of the binder is 10 - 20.0 wt%.

[0271] In some embodiments, the content of the antioxidant is preferably 0.5 - 2.0 wt%, such as 1.47 - 1.66 wt%.

[0272] In some embodiments, the content of the plasticizer is preferably 1 - 2 wt%, such as 1.0 wt%.

[0273] In some embodiments, in the immediate-release drug-containing outer coating, the drug active ingredient includes levodopa and / or carbidopa. Wherein, when there are two drug active ingredients, the mass of levodopa is 12.5 - 200 mg; the mass of carbidopa is 10.5 - 200 mg. The mass ratio of levodopa to carbidopa is preferably 1:1 - 4:1.

[0274] In some embodiments, in the drug-containing immediate-release outer coating, the masses of levodopa and carbidopa are 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, respectively. If carbidopa is used in the form of carbidopa monohydrate, the mass of carbidopa here is correspondingly replaced by the mass of carbidopa monohydrate (which can be replaced proportionally according to the mass of carbidopa).

[0275] Preferably, the drug-containing immediate-release outer coating comprises a drug active ingredient and an excipient, and the excipient is hydroxypropyl cellulose (EXF) as a binder. In some embodiments, the content of the drug active ingredient is preferably 80 - 90 wt%. In some embodiments, the content of the binder is 10 - 20.0 wt%.

[0276] 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 hydroxypropyl cellulose (EXF).

[0277] 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 hydroxypropyl cellulose (EXF).

[0278] 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 hydroxypropyl cellulose (EXF).

[0279] In some embodiments, the drug-containing immediate-release outer coating comprises 90.0 wt% of carbidopa monohydrate and 10.0 wt% of hydroxypropyl cellulose (EXF).

[0280] Another aspect of the present disclosure relates to an osmotic pump tablet, which includes any of the following schemes:

[0281] Scheme (A): 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 a drug release hole. 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

[0282] Scheme (B): 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 a drug release hole. The tablet core includes a drug-containing layer, and the drug-containing layer contains a drug active ingredient and an excipient. The drug-containing rapid-release outer coating contains a drug active ingredient and a pharmaceutical excipient, and the pharmaceutical excipient is a binder.

[0283] In Scheme (A), both the drug active ingredient and the excipient are those mentioned in the present disclosure.

[0284] In Scheme (A), the drug active ingredient preferably includes levodopa and / or carbidopa. In Scheme (A), when the drug active ingredient contains levodopa, based on the total weight of the drug-containing layer, the content of levodopa is 19.5 - 75 wt%; for example, 19.5 - 70 wt% (such as 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 contains carbidopa, based on the total weight of the drug-containing layer, the content of carbidopa is 0 - 20 wt% but not 0%, for example, 10% - 20% (such as 10.8 wt% of carbidopa monohydrate).

[0285] In Scheme (A), based on the total weight of the drug-containing layer, the content of the drug active ingredient is 30 - 75 wt%, for example, 38 wt% - 65 wt% (such as 38 wt%, 39.5 wt%, 40 wt%, 45 wt%, 50 wt% or 70 wt%).

[0286] In Scheme (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%; for example, 0.5 - 20 wt%, and further for example, 5 - 10 wt%.

[0287] In Scheme (A), the hydrophilic polymer may also be a mixture of povidone K29 / 32 and one or more selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and hydroxyethyl cellulose.

[0288] In Scheme (A), the excipient is selected from one or more of a filler, an osmotic agent, a sour agent, a lubricant, and a flavoring agent.

[0289] Preferably, when the auxiliary materials contain 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%, such as 31 wt%.

[0290] Preferably, when the auxiliary materials contain a penetrant, 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 drug-containing layer, the content of the penetrant is preferably 0-50 wt% but not 0%; for example, 4-50 wt%; such as 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%.

[0291] Preferably, when the auxiliary materials contain 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%.

[0292] Preferably, when the auxiliary materials contain a lubricant, the lubricant is one or more of magnesium stearate, magnesium stearoyl fumarate, talc, and colloidal silica, such as one or two of magnesium stearate and colloidal silica. Based on the total weight of the drug-containing layer, the content of the lubricant is 0.5-3 wt%; for example, 0.5-2.5 wt%, such as 1-2 wt%.

[0293] Preferably, when the auxiliary materials contain a flavoring agent, the flavoring agent is one or more of aspartame (also known as 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 drug-containing layer, the content of the flavoring agent is 0-10 wt%, but not 0; for example, 1-6 wt%; such as 2-5 wt%.

[0294] In Scheme (A), the auxiliary materials are preferably any one of the following combinations: (1) filler, penetrant, hydrophilic polymer, acidulant and lubricant; (2) filler, hydrophilic polymer and lubricant; (3) filler, penetrant, hydrophilic polymer, lubricant and flavoring agent; (4) penetrant, hydrophilic polymer and lubricant; (5) filler, hydrophilic polymer, penetrant and lubricant; (6) filler, penetrant, acidulant and lubricant; (7) filler, penetrant, flavoring agent and lubricant; and (8) filler, acidulant and lubricant. The auxiliary materials are preferably filler, hydrophilic polymer, penetrant and lubricant.

[0295] In Scheme (A), the drug-containing layer contains 30 - 75 wt% of the drug active ingredient, 0.5 - 20 wt% of the hydrophilic polymer, 20 - 50 wt% of the filler, 4 - 50 wt% of the penetrant and 0.5 - 3 wt% of the lubricant; for example, it contains 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone K29 / 32, 18.0 wt% of mannitol and 1.00 wt% of magnesium stearate; or, it contains 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone K29 / 32, 16.5 wt% of mannitol, 0.50 wt% of colloidal silicon dioxide and 2.00 wt% of magnesium stearate.

[0296] In Scheme (A) and Scheme (B), the tablet core 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. The coating film is wrapped outside the tablet core. In the present disclosure, the boosting layer and the osmotic pushing layer mentioned above have the same meaning and can be replaced with each other. The boosting layers in the osmotic pump tablets are all those mentioned in the present disclosure.

[0297] In Scheme (A) and Scheme (B), the coating films in the osmotic pump tablets are all those mentioned in the present disclosure.

[0298] In Scheme (A) and Scheme (B), the osmotic pump tablets further include a barrier layer. The barrier layers are all those mentioned in the present disclosure.

[0299] In Scheme (A), the outside of the osmotic pump tablet may further include a drug-containing rapid-release outer coating. The drug-containing rapid-release layers in the osmotic pump tablets are all those mentioned in the present disclosure.

[0300] In Scheme (B), in the drug-containing rapid-release outer coating, the binder is preferably hydroxypropyl cellulose (EXF).

[0301] In Scheme (B), in the drug-containing rapid-release outer coating, except for the pharmaceutical excipients, the drug-containing rapid-release layers in the osmotic pump tablets are all those mentioned in the present disclosure.

[0302] In solution (B), in the drug-containing immediate-release outer coating, the content of the drug active ingredient is preferably 80-90 wt%; the content of the pharmaceutical excipient is preferably 10-20.0 wt%.

[0303] In solution (B), in the drug-containing immediate-release outer coating, the drug active ingredient comprises levodopa and / or carbidopa, wherein when there are two drug active ingredients, the mass ratio of levodopa to carbidopa is preferably 1:1-4:1.

[0304] In solution (B), the drug-containing layers in the osmotic pump tablets are all those mentioned in the present disclosure.

[0305] In solution (B), the drug-containing layer is preferably any one of the following combinations:

[0306] (1) 30-75 wt% of drug active ingredient, 20-50 wt% of filler, 4-50 wt% of osmotic agent, 0.5-20 wt% of hydrophilic polymer, 5-10 wt% of sour agent and 0.5-3 wt% of 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) and 5.0 wt% of citric acid and 0.5 wt% of magnesium stearate;

[0307] (2) 30-75 wt% of drug active ingredient, 20-50 wt% of filler, 0.5-20 wt% of hydrophilic polymer and 0.5-3 wt% of lubricant; such as 38.0 wt% of levodopa, 50.0 wt% of microcrystalline cellulose, 10.0 wt% of hydroxypropyl methylcellulose and 2.0 wt% of magnesium stearate;

[0308] (3) 30-75 wt% of drug active ingredient, 20-50 wt% of filler, 4-50 wt% of osmotic agent, 5-10 wt% of sour agent and 0.5-3 wt% of lubricant; such as 40.0 wt% of levodopa, 10.8 wt% of carbidopa monohydrate, 31.0 wt% of hydroxypropyl cellulose with 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;

[0309] (4) 30 - 75 wt% of the pharmaceutically active ingredient, 20 - 50 wt% of the filler, 4 - 50 wt% of the permeation enhancer, 0.5 - 20 wt% of the hydrophilic polymer, 0.5 - 3 wt% of the lubricant, and 1 - 6 wt% of the flavoring agent; for example, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (Klucel EXF), 16.0 wt% of mannitol, 5.0 wt% of polyvinylpyrrolidone K30, 1.0 wt% of aspartame, 1.0 wt% of peppermint essence, and 1.0 wt% of magnesium stearate; or 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose, 17.0 wt% of mannitol, 5.0 wt% of polyvinylpyrrolidone K30, 1.0 wt% of magnesium stearate, and 1.0 wt% of aspartame; or 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose, 17.0 wt% of mannitol, 5.0 wt% of polyvinylpyrrolidone K30, 1.0 wt% of magnesium stearate, and 1.0 wt% of aspartame;

[0310] (5) 30 - 75 wt% of the pharmaceutically active ingredient, 4 - 50 wt% of the permeation enhancer, 5 - 20 wt% of the hydrophilic polymer, and 0.5 - 3 wt% of the lubricant; for example, 70.0 wt% of levodopa, 9.0 wt% of mannitol, 20.0 wt% of polyvinylpyrrolidone K30, and 1.0 wt% of magnesium stearate;

[0311] (6) 30 - 75 wt% of the pharmaceutically active ingredient, 20 - 50 wt% of the filler, 4 - 50 wt% of the permeation enhancer, 1 - 6 wt% of the flavoring agent, and 0.5 - 3 wt% of the lubricant; for example, 20.0 wt% of levodopa, 20.0 wt% of carbidopa, 50.0 wt% of hydroxypropyl cellulose, 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 hydroxypropyl cellulose, 22.0 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of peppermint essence, and 1.0 wt% of magnesium stearate;

[0312] (7) 30 - 75 wt% of the pharmaceutically active ingredient, 20 - 50 wt% of the filler, 5 - 10 wt% of the acidulant, and 0.5 - 3 wt% of the 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;

[0313] (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 a penetrant, and 0.5 - 3 wt% of a lubricant; for example, 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (such as hydroxypropyl cellulose EXF), 5.00 wt% of polyvinylpyrrolidone (such as polyvinylpyrrolidone 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 (such as hydroxypropyl cellulose EXF), 5.00 wt% of polyvinylpyrrolidone (such as polyvinylpyrrolidone K29 / 32), 16.5 wt% of mannitol, 0.50 wt% of colloidal silicon dioxide, and 2.00 wt% of magnesium stearate.

[0314] One of the technical solutions of the present invention is: an application of the osmotic pump tablet as described above in the preparation of a drug for treating motor symptom fluctuations in patients with advanced Parkinson's disease.

[0315] One of the technical solutions of the present invention is: a preparation method of the osmotic pump tablet as described above, and the preparation method of the osmotic pump tablet comprises the following steps:

[0316] S1. Prepare the drug-containing layer granules, which includes the following steps: mix the pharmaceutically active ingredient and excipients, and granulate to obtain the drug-containing layer granules;

[0317] 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;

[0318] S3. Prepare the double-layer tablet core, and tablet the drug-containing layer granules and the boosting layer granules obtained in step S1 and step S2 to obtain the double-layer tablet core;

[0319] S4. Prepare the osmotic pump tablet, wrap the tablet core with a coating film, and drill a drug release hole to obtain it;

[0320] S5. Optionally, after the end of step S4, it further includes the step of wrapping a drug-containing immediate-release outer coating outside the osmotic pump tablet;

[0321] Optionally, after step S3 and before step S4, it further includes the step of preparing a separating layer; the step of preparing the separating layer includes tableting the separating layer material and the double-layer tablet core;

[0322] Step S5 is essential in Scheme (B).

[0323] The preparation method of the osmotic pump tablet preferably includes the following steps:

[0324] S1. Prepare the drug-containing layer granules, which includes the following steps: Mix the drug active ingredient, hydrophilic polymer, and surfactant, optionally mix with other excipients, and granulate to obtain the drug-containing layer granules;

[0325] S2. Prepare the boosting layer granules, which includes the following steps: Granulate at least one of the swelling agent, penetrant, binder, lubricant, and colorant to obtain the boosting layer granules;

[0326] S3. Prepare the double-layer tablet core, and compress the drug-containing layer granules and the boosting layer granules obtained in step S1 and step S2 to obtain the double-layer tablet core;

[0327] S4. Prepare the osmotic pump tablet, wrap the tablet core with a coating film, and drill a drug release hole to obtain it.

[0328] In some embodiments, in step S1 and step S2, preferably, before the mixing, it includes the step of screening each component. The screening is preferably carried out through a 40-mesh sieve. The granulation is independently dry granulation, wet granulation, or fluidized bed granulation. When wet granulation is used, it is preferably dried by a fluidized bed after granulation. Preferably, after granulation, it includes the step of sizing. The sizing is preferably carried out through a 1.2-mm sieve.

[0329] In some embodiments, in step S3, the method of tableting can be a conventional method in the art. The tableting punch die used preferably is a 7.0-mm round punch.

[0330] In some embodiments, the drug release hole is obtained by laser drilling or mechanical drilling.

[0331] In some embodiments, in step S1, when the drug active ingredient contains levodopa and carbidopa, it preferably includes the following steps:

[0332] (a) Mix levodopa, hydrophilic polymer, binder (or drug carrier) or penetrant, and flavoring agent, and granulate to obtain levodopa-containing granules;

[0333] (b) Mix carbidopa monohydrate, surfactant, and penetrant, and granulate to obtain carbidopa-containing granules;

[0334] (c) After mixing the granules obtained in step (a) and step (b), mix with lubricant and flavoring agent, optionally mix with antioxidant, to obtain the drug-containing layer granules.

[0335] Specifically, mix the raw material components of the drug-containing immediate-release outer coating and an alcohol solvent to obtain a solution, and then spray the obtained solution onto the osmotic pump tablet. Among them, the alcohol solvent is preferably ethanol. The solid content of the obtained solution is about 10 wt% (the solid content refers to the sum of the weights of all solid components of the coating solution divided by the total weight of the coating solution).

[0336] Another technical solution of the present disclosure is: a method for using the above osmotic pump tablets, that is, placing the osmotic pump tablets in the oral retention device or oral medicator for combined use.

[0337] On the basis of conforming to the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present disclosure.

[0338] The reagents and raw materials used in the present disclosure are all commercially available.

[0339] The positive and progressive effects of the present invention are as follows:

[0340] The osmotic pump tablets of the present disclosure have at least any of the following characteristics:

[0341] (1) It can be maintained in the oral cavity for 2 - 24 hours, and 85% of the active drug is released in 4 - 24 hours, for example, 5 - 16 hours, and the drug can be continuously released in the oral cavity;

[0342] (2) During the drug release process, the active drug ingredient will quickly enter the digestive tract, and it is not easy to stay and accumulate in the oral cavity. The retention amount of the active drug ingredient at 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%;

[0343] (3) The coating film for controlled release will not break; the residue of the active drug ingredient in the osmotic pump tablet is less than 15%;

[0344] (4) The released active drug ingredient is continuously swallowed into the gastrointestinal tract, providing continuous drug absorption and stable blood drug concentration;

[0345] (5) The osmotic pump tablet can also include a drug - containing rapid - release outer coating, and the in - vivo drug release amount and blood drug concentration can be conveniently adjusted, quickly reaching the therapeutic concentration and maintaining within the therapeutic concentration range for 5 - 16 hours;

[0346] (6) The active drug ingredient in a single - piece osmotic pump tablet can reach a large dose of 200 - 2000 mg; in particular, when the active drug ingredient contains levodopa, the drug - loading amount of levodopa can be as high as 200 mg - 1500 mg; when the active drug ingredient contains carbidopa, the drug - loading amount of carbidopa can reach 1 mg - 200 mg;

[0347] (7) The drug - loading amount of the active drug ingredient in the drug - containing layer can be as high as 50 - 75%;

[0348] (8) The drug permeation amount in the tablet in an aqueous medium is 8 - 150 mg / h (the permeation amount refers to the milligram number of the drug released in the dissolution experiment per hour per unit time). Description of the Drawings

[0349] Figure 1A and 1B Schematic diagrams of controlled release platforms (ERPs): Figure 1A . Single-layer basic osmotic pump (EOP); Figure 1B . Double-layer osmotic push-pull system.

[0350] Figure 2 Schematic diagrams of controlled release dosage forms (combinations of controlled release platforms ERPs and retention platforms REPs): 1. Personalized retention components of the retention platform (REP); 2. Controlled release platform (ERP); 3. Drug fixation components of the retention platform (REP).

[0351] Figures 3A - 3C Flow chart for manufacturing the controlled release dosage form (ERP + REP) of the present invention: Figure 3A . Controlled release dosage form with a single-layer basic osmotic pump (EOP) as the controlled release platform; Figure 3B . Controlled release dosage form with a double-layer osmotic push-pull system as the controlled release platform; Figure 3C . Controlled release dosage form with a double-layer push-pull system with a fast-release drug coating as the controlled release platform.

[0352] Figure 4 Preparation of the retention platform (REP) described in Example 1: Figure 4 A. Drug fixation components; Figure 4 B. Drug fixation components; Figure 4 C. Drug fixation components; Figure 4 D. Drug fixation components; Figure 4 E. Thermoplastic sheet; Figure 4 F. Personalized retention platform (REP).

[0353] Figure 5 Drug fixation components described in Example 1: Figure 5 A. Drug fixation components; Figure 5 B. The controlled release platform is fixed in the drug fixation components.

[0354] Figure 6 Retention platforms (REPs) described in Example 2 and Example 3: Figure 6 A. Retention platform (REP); Figure 6 B. The controlled release platform is fixed to the retention platform (REP); Figure 6 C. Retention platform (REP) with a self-locking lid; Figure 6 D. The controlled release platform is fixed to the retention platform (REP); Figure 6 E. Controlled release platform + retention platform (REP) with the lid closed; Figure 6 F. Retention platform (REP) with a flip-up lid; Figure 6 G. The controlled release platform is fixed to the retention platform (REP); Figure 6H. Controlled Release Platform + Retention Platform (REP) with Cover Closed; Figure 6 I. Retention Platform (REP) with Slidable Cover; Figure 6 J. Controlled Release Platform Fixed to Retention Platform (REP); Figure 6 K. Controlled Release Platform + Retention Platform (REP) with Cover Closed.

[0355] Figure 7 For the Retention Platform (REP) described in Example 4 and Example 5: Figure 7 A. Retention Platform (REP); Figure 7 B. Controlled Release Platform Fixed to Retention Platform (REP).

[0356] Figure 8 Release curves for the Controlled Release Platform (ERP) described in Example 6. Error bars represent standard deviation for n = 3.

[0357] Figure 9 Release curves for the Controlled Release Platform (ERP) described in Example 7. Error bars represent standard deviation for n = 3.

[0358] Figure 10 Release curves for the Controlled Release Platform (ERP) described in Example 8. Error bars represent standard deviation for n = 3.

[0359] Figure 11 Release curves for the Controlled Release Platform (ERP) described in Example 9. Error bars represent standard deviation for n = 3.

[0360] Figure 12 Release curves for the Controlled Release Platform (ERP) described in Example 10. Error bars represent standard deviation for n = 3.

[0361] Figure 13 Release curves for the Controlled Release Platform (ERP) described in Example 11. Error bars represent standard deviation for n = 3.

[0362] Figure 14 Release curves for the Controlled Release Platform (ERP) described in Example 12. Error bars represent standard deviation for n = 3.

[0363] Figure 15 Release curves for the Controlled Release Platform (ERP) described in Example 13. Error bars represent standard deviation for n = 3.

[0364] Figure 16 Release curves for the Controlled Release Platform (ERP) described in Example 23. Error bars represent standard deviation for n = 3.

[0365] Figure 17Release curves for the extended release platform (ERP) described in Example 24. Error bars represent standard deviation for n = 3.

[0366] Figure 18 Release curves for the extended release platform (ERP) described in Example 25. Error bars represent standard deviation for n = 3.

[0367] Figure 19 Release curves for the extended release platform (ERP) described in Example 26. Error bars represent standard deviation for n = 3.

[0368] Figure 20 Release curves for the extended release platform (ERP) described in Example 27. Error bars represent standard deviation for n = 3.

[0369] Figure 21 Release curves for the extended release dosage form (ERP + REP) described in Example 29. Error bars represent standard deviation for n = 3.

[0370] Figure 22 The post-insertion oral retention device of a tablet according to an embodiment of the present invention is composed of a tooth engagement member 11 and a drug-loading member 41. Among them, the drug-loading member 41 is composed of a limiting member 21 and a ring body 31, and there is an opening 311 on the ring body 31.

[0371] Figure 23 The pre-insertion oral retention device of a tablet according to an embodiment of the present invention is composed of a tooth engagement member 12 and a drug-loading member 42. Among them, the drug-loading member 42 is composed of a limiting member 22 and a ring body 32, and there is an opening 321 on the ring body 32.

[0372] Explanation of reference numerals:

[0373] 11: Tooth engagement member of the post-insertion oral retention device

[0374] 21: Limiting member of the post-insertion oral retention device

[0375] 31: Ring body of the post-insertion oral retention device

[0376] 311: Opening on the ring body of the post-insertion oral retention device

[0377] 41: Drug-loading member of the post-insertion oral retention device

[0378] 12: Tooth engagement member of the pre-insertion oral retention device

[0379] 22: Limiting member of the pre-insertion oral retention device

[0380] 32: Ring body of the pre-insertion oral retention device

[0381] 321: Opening on the annular body of the front-inserted oral retention device

[0382] 42: Drug-carrying component of the front-inserted oral retention device

[0383] Figure 24 Schematic diagrams of the structures of the components of the oral drug dispenser according to Embodiment 35 of the present invention, which is composed of a core component 1 and a fixing device 2. Among them, 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 is composed of a first ring 121 and a second ring 122.

[0384] Figure 25 Schematic diagram of the structure of the core component in the oral drug dispenser according to Embodiment 35 of the present invention.

[0385] Figure 26 Schematic diagram of the structure of the fixator when the fixing device is a fixator in the oral drug dispenser according to Embodiment 35 of the present invention.

[0386] Figure 27 For the Figure 24 Cross-sectional view along the A-A plane.

[0387] Figure 28 Schematic diagram of the structure of the oral drug dispenser according to Embodiment 36.

[0388] Figure 29 Schematic diagram of the structure of the oral drug dispenser according to Embodiment 37.

[0389] Figure 30 Schematic diagram of the structure of the oral drug dispenser according to Embodiment 40.

[0390] Figure 31 For the Figure 30 Cross-sectional view along the B-B plane.

[0391] Figure 32 Schematic diagram of the structure of the oral drug dispenser according to Embodiment 43.

[0392] Explanation of the reference numerals is as follows:

[0393] 1 - Core component; 2 - Fixing device; 201 - Lingual side of the fixing device; 202 - Buccal side of the fixing device; 203 - Occlusal surface of the fixing device; 11 - Molar anastomosis functional area; 12 - Drug-carrying functional area; 121 - First ring; 122 - Second ring; 123 - Clamping wall.

[0394] Figure 33 Release curve of the osmotic pump tablet according to Embodiment 47 of the present invention.

[0395] Figure 34 Release curve of the osmotic pump tablet according to Embodiment 48 of the present invention.

[0396] Figure 35 Release curve of the osmotic pump tablet of Example 49 of the present invention.

[0397] Figure 36 Release curve of the dosage form of Example 50 of the present invention.

[0398] Figure 37 Release curve of the osmotic pump tablet of Example 51 of the present invention.

[0399] Figure 38 Release curve of the osmotic pump tablet of Example 52 of the present invention.

[0400] Figure 39 Release curve of the osmotic pump tablet of Example 57 of the present invention.

[0401] Figure 40 Release curve of the osmotic pump tablet of Example 58 of the present invention.

[0402] Figure 41 Release curve of the osmotic pump tablet of Example 59 of the present invention.

[0403] Figure 42 Release curve of the osmotic pump tablet of Example 60 of the present invention.

[0404] Figure 43 Release curve of the osmotic pump tablet of Example 61 of the present invention.

[0405] Figure 44 Release curve of the osmotic pump tablet of Example 62 of the present invention.

[0406] Figure 45 Release curve of the osmotic pump tablet of Example 63 of the present invention.

[0407] Figure 46 Release curve of the osmotic pump tablet of Example 64 of the present invention.

[0408] Figure 47 Soaking experiment of the osmotic pump tablet of Comparative Example A.

[0409] Figure 48 Release curve of the osmotic pump tablet of Comparative Example A.

[0410] Figure 49 Release curve of the osmotic pump tablet of Comparative Example B. Detailed implementation manners

[0411] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. The experimental methods without specific conditions in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0412] The following are preferred embodiments, and the present disclosure will be more clearly and completely described in conjunction with the accompanying drawings. It should be noted that: unless otherwise specified, the relative arrangements and numerical values of the components and steps set forth in these embodiments do not limit the scope of the present disclosure. The present disclosure is further illustrated by way of examples below, but is not thereby limited to the scope of the described embodiments. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or according to the product specifications. The pharmaceutical active ingredients (APIs) used in the present disclosure include, but are not limited to, levodopa / carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin.

[0413] In one embodiment, the pharmaceutical active ingredient (API) is levodopa and / or carbidopa, which is incorporated into a single-layer elementary osmotic pump (EOP) known in the prior art (U.S. Patent Nos. 3,845,770 and 3,916,899). As Figure 1A shown, the EOP includes a tablet core containing the API and a rate-controlling membrane surrounding the tablet core. The EOP includes at least one hole through the membrane such that LD / CD can be released through the hole into the oral cavity. The tablet core includes LD / CD, an osmotic agent, microcrystalline cellulose (MCC), a binder, a lubricant, a flavoring agent (optionally), an acidifying agent (optionally), and an antioxidant (optionally). The rate-controlling membrane includes a semipermeable polymer that is fully or at least partially permeable to water or moisture present in the oral cavity, while being substantially impermeable to the drug and other optional components that may be present in the core. A representative semipermeable polymer is cellulose acetate with an acetyl content of 32.0 - 39.8 wt%.

[0414] In another embodiment, LD / CD is incorporated into a bilayer osmotic delivery system (push-pull) known in the prior art (U.S. Patent Nos. 4,327,725 and 4,612,008). As Figure 1B shown, the push-pull system includes two layers of cores (a drug-containing pulling layer and an osmotic pushing layer) and a rate-controlling membrane surrounding the cores. The push-pull system includes at least one hole through the membrane on the side of the drug-containing layer such that the contents of the pulling layer can be released through the hole into the oral cavity. The pulling layer includes LD / CD, a hydrophilic polymer, an osmotic agent, a binder, a lubricant, a flavoring agent (optionally), an acidifying agent (optionally), an antioxidant (optionally). The pushing layer includes a high molecular weight hydrophilic polymer, an osmotic agent, a binder, a lubricant, and a coloring agent (optionally). The push-pull osmotic delivery system operates by sucking water or moisture through the rate-controlling membrane into the bilayer core, where it hydrates the two layers, causing the osmotic pushing layer to expand and push the hydrated, dispensable drug-containing layer formulation through the orifice from the system.

[0415] Figure 2It 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 fixation component. The retention component can be customized to fit the corresponding tooth. The drug fixation component fixes the controlled-release platform ERP as a reservoir 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 tooth parts. Due to the length of the retention platform REP, its (REP that holds the ERP) is in a non-inhalable position, thus eliminating the possibility of obstruction. The preferred structure of the REP is a snap-on or nut-type basket with various mesh sizes to prevent the ERP from falling out. Other structures of the REP can be, but are not limited to, a retainer with two clamping arms.

[0416] Figures 3A - 3C The flowchart shows the manufacturing of the controlled-release dosage form (ERP + REP) of the present disclosure. Figure 3A The flowchart shows the manufacturing of a controlled-release dosage form with a single-layer basic osmotic pump (EOP) as the controlled-release platform; Figure 3B The flowchart shows the manufacturing of a controlled-release dosage form with a double-layer osmotic push-pull system as the controlled-release platform; Figure 3B The flowchart shows the manufacturing of a controlled-release dosage form with a double-layer push-pull system with a fast-release drug coating as the controlled-release platform.

[0417] The retention component REP can be made of polymeric materials or dental titanium using 3D printing technology, injection molding, or impression molding. Polymeric materials include, but are not limited to, polycaprolactone (PCL), ethylene-vinyl acetate copolymer (EVA), high-density polyethylene (HDPE), polypropylene (PP), polyacrylate, and any other tissue-compatible polymers. PCL has advantages such as a low melting point and good biocompatibility, and is a good material. Therefore, the personalized retention component of the REP made of PCL is easily softened in hot water and then fits the molar or premolar.

[0418] One of the ERPs in the present disclosure is a single-layer basic osmotic pump and can be manufactured by standard manufacturing techniques. First, in a conventional wet granulation method, a core granulation can be prepared using a high-shear granulator or a fluidized-bed granulator. Second, the granules are pressed into a single-layer core tablet in a press. Next, the core tablet is coated with a coating composition of a coating film. Finally, a channel is drilled through the coating film.

[0419] Another ERP in the present disclosure is a double-layer push-pull osmotic pump and can be manufactured as follows. First, a drug-containing layer granulation and an osmotic push layer granulation can be prepared using a high-shear granulator or a fluidized-bed granulator. Second, the granules of these two layers are pressed into a double-layer core tablet in a press. Next, the double-layer core tablet is coated with a coating composition of a coating film, followed by a drying process. Finally, a channel is drilled through the coating film on the drug-containing layer side.

[0420] The coating film of the osmotic dosage form can be formed using an air suspension technique. The method includes 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 co-solvent 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 by continuously spraying the composition onto the tablet core while tumbling in a rotating pan. Generally, the films formed by these techniques have a thickness of 25 to 250 μm, and the preferred thickness is 100 to 150 μm.

[0421] Optionally, the drilled single-layer EOP or double-layer push-pull system can be coated with an immediate-release LD / CD drug layer.

[0422] The personalized retention platform (REP) in the present disclosure can be manufactured as follows. The REP is prepared by 3D printing technology. First, an oral image of an individual is obtained through an oral scanner. Next, the REP, i.e., the retainer of the ERP, is designed using CAD / CAM software. Then, according to the CAD / CAM design, the REP is manufactured from a tissue-compatible polymer or dental titanium, or cobalt-chromium alloy, or cobalt-chromium-molybdenum alloy using 3D printing technology or an injection molding process.

[0423] The personalized retention platform (REP) in the present disclosure can also be manufactured by an injection molding technology. First, a mold is taken using a dental impression material to prepare a plaster tooth model identical to the patient's; secondly, a dental wax REP shape is prepared on the plaster tooth model using a conventional process with dental wax; then the above dental wax REP is wrapped with a mixture of embedding powder and water, and after standing and curing, it is heated to melt the embedded dental wax to obtain an injection mold cavity in the shape of the REP; finally, at a certain temperature, the completely molten cobalt-chromium alloy is poured into the above mold cavity, and after cooling and curing, it is polished.

[0424] The personalized retention platform (REP) in the present disclosure can also be manufactured by an impression molding technology. First, a drug fixation component is manufactured, and secondly, an oval thermoplastic sheet is processed by a conventional process. Then the thermoplastic sheet is heated to soften it, and the softened thermoplastic sheet is pressed to completely wrap the tooth, forming a personalized retention component that fits perfectly with the tooth. Then the drug fixation component is quickly embedded onto the uncured retention component and cooled and cured into a personalized retention platform (REP). Wait for the personalized retention platform to cool and return to its original opaque hard sheet state, and then remove the cooled personalized retention platform from the oral cavity.

[0425] Preparation of the retention platform in Example 1 (impression molding)

[0426] 1. Prepare a drug fixation component made of stainless steel, titanium for dental use, cobalt-chromium alloy, or cobalt-chromium-molybdenum alloy that is suitable for the controlled release platform, such as Figure 4 A. Figure 4 B. Figure 4 C. Figure 4 As shown in D, its shape can be one or more reservoirs that are open at one or both ends, and the cross-sectional shape of the reservoir can be polygonal, circular closed-loop, or open-loop with an opening smaller than the minimum diameter of the tablet.

[0427] 2. Process 50 grams of polycaprolactone into an oval thermoplastic sheet with dimensions of 2.5 CM × 1.5 CM through conventional processes (such as Figure 4 E);

[0428] 3. Preparation of personalized REP: Heat a thermoplastic sheet in hot water at about 70 °C to make it soft and have good plasticity. When the thermoplastic sheet becomes translucent (about 1 minute), take it out and place it on the tooth, press the softened thermoplastic sheet to completely wrap the tooth and form a retention component that fits perfectly with the tooth. Then quickly embed the stainless steel drug fixation component onto the uncured retention component and cool and solidify it into a personalized retention platform (REP). Sprinkle 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 take out the cooled personalized retention platform from the oral cavity (such as Figure 4 F).

[0429] Figure 5 For the above drug fixation component: Figure 5 A. Drug fixation component; Figure 5 B. The controlled release platform is fixed in the drug fixation component.

[0430] Example 2 Preparation of the retention platform (injection molding)

[0431] Prepare a retention platform that fits the interdental space of the mandibular molar through injection molding process according to the following steps, see Figure 6 .

[0432] First, take a mold using dental impression material to prepare a plaster tooth model that is the same as the patient;

[0433] Use dental wax to prepare the shape of the dental wax REP on the plaster tooth model through conventional processes;

[0434] Then wrap the above dental wax REP with a mixture of embedding powder and water, let it stand and solidify, and then heat to melt the embedded dental wax to obtain an injection mold cavity with the shape of REP;

[0435] At a certain temperature, pour the completely molten cobalt-chromium alloy into the above mold cavity, cool and solidify it, and then grind and polish.

[0436] Example 3 Preparation of Retention Platform (3D Printing)

[0437] Follow the steps below to prepare a retention platform that fits the interdental spaces of mandibular molars through oral scanning and 3D printing process, as shown in Figure 6 .

[0438] First, obtain an oral image of an individual through an oral scanner;

[0439] Use CAD / CAM software or dental software to process the scanned data, generate an electronic tooth model, convert it into an editable file, and design a personalized retention platform device that fits the teeth perfectly;

[0440] Use cobalt-chromium-molybdenum 3D printing material to print the designed personalized device through the laser sintering technology of a 3D printer.

[0441] Example 4 Preparation of Retention Platform (Injection Molding)

[0442] Follow the steps below to prepare a retention platform that fits the non-occlusal periphery of mandibular molars through injection molding process, as shown in Figure 7 .

[0443] First, take a mold with dental impression material to prepare a plaster tooth model identical to the patient;

[0444] Use dental wax to prepare the shape of dental wax REP on the plaster tooth model through conventional processes;

[0445] Then wrap the above dental wax REP with a mixture of embedding powder and water, let it stand and solidify, and then heat to melt the embedded dental wax to obtain an injection mold cavity in the shape of REP;

[0446] At a certain temperature, pour the completely molten cobalt-chromium alloy into the above mold cavity, and after cooling and solidifying, polish it.

[0447] Example 5 Preparation of Retention Platform (3D Printing)

[0448] Follow the steps below to prepare a retention platform that fits the non-occlusal periphery of mandibular molars through oral scanning and 3D printing process, as shown in Figure 7 .

[0449] First, obtain an oral image of an individual through an oral scanner;

[0450] Use CAD / CAM software or dental software to process the scanned data, generate an electronic tooth model, convert it into an editable file, and design a personalized retention platform device that fits the teeth perfectly;

[0451] Use cobalt-chromium-molybdenum 3D printing material to print the designed personalized device through the laser sintering technology of a 3D printer.

[0452] Preparation of the controlled release platform of Example 6

[0453] A dosage form for delivering the beneficial drugs levodopa and carbidopa to the oral cavity is manufactured as follows: First, a tablet core is prepared, including 40.0 wt% levodopa (LD), 10.8 wt% carbidopa monohydrate (CD), 20.0 wt% microcrystalline cellulose, 18.7 wt% mannitol, 5.0 wt% hydroxypropyl methylcellulose (HPMC E5), and 5.0 wt% citric acid, by weight percentage. They are respectively passed through a 40-mesh stainless steel sieve, then mixed with pure 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% magnesium stearate.

[0454] Next, using a tableting machine, 500 mg of the core granules are pressed into a single-layer tablet core with a 9.0 mm round punch.

[0455] Next, the single-layer tablet core is coated with a coating film. The film-forming composition contains 50 wt% cellulose acetate and 50 wt% copovidone VA 64, by weight percentage. The film-forming composition is dissolved in acetone to make a 4% solid solution. Using the process parameters listed in the following table, the film-forming composition is sprayed onto the tablet core in a Glatt GC 1 pan coater to form a coating film (the process parameters of the coating process are shown in Table 1). The film weight gain of the coated tablets is 2.0%. Finally, an outlet hole with a diameter of 0.5 mm is mechanically drilled on the drug layer side of the coated tablets. The residual solvent is removed by drying the dosage form at 40 °C and ambient humidity for 24 hours. The release curve of the finally manufactured dosage form is measured in an aqueous solution of 0.1 N HCl using a USPI sieve plate. As Figure 8 shown, the finally manufactured dosage form ERP delivers LD and CD at an average rate of 14.17 mg / hr and 4.59 mg / hr, respectively, and 85% of the drugs are delivered at 12 hours and 10 hours, respectively. This ERP osmotic delivery system can be retained in the oral cavity until the push layer reaches the delivery port; or be retained there for 8 - 9 hours and then swallowed; or be fixed on the teeth that match the oral cavity after being combined with the retention platform REP and be retained there for 12 hours.

[0456] Table 1

[0457]

[0458] Preparation of the controlled release platform of Example 7

[0459] A dosage form designed, shaped, and adapted to dispense the beneficial drugs levodopa and carbidopa monohydrate into the oral cavity is prepared as follows: First, a drug layer composition is prepared, which contains 40.0 wt% of LD, 10.8 wt% of CD, 31.0 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 12.7 wt% of mannitol, and 5.0 wt% of citric acid. These excipients are each sieved through a 40-mesh stainless steel sieve, then mixed with 95% ethanol 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.

[0460] Next, a second composition, namely the osmotic layer, is prepared, which contains 55.0 wt% of sodium carboxymethyl cellulose 7H4XF, 39.0 wt% of sorbitol, 5.0 wt% of polyvinylpyrrolidone K30, and 0.5 wt% of iron oxide red; these components are each sieved through a 40-mesh stainless steel sieve, then mixed with 95% ethanol 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.

[0461] Next, the drug layer and osmotic layer granules are compressed into a bilayer tablet core. First, 500 mg of the drug layer granules are added to a 9-mm round punch of a tablet press and tamped, then 250 mg of the osmotic layer granules are added to the punch, and the granules of the two layers are compressed by the tablet press to form a contact bilayer tablet core.

[0462] Next, a coating film is wrapped around the bilayer tablet core. The film-forming composition contains 70 wt% of cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% of copolyvinylpyrrolidone VA 64 by weight percentage. The film-forming composition is dissolved in acetone to make a 4% solid solution. Using the process parameters listed in Example 6, the film-forming composition is sprayed onto the bilayer tablet core in a Glatt GC 1 pan coater to form a coating film, and the film weight gain of the coated tablet is 5.0%. Finally, an exit hole with a diameter of 0.5 mm is mechanically drilled on the drug layer side of the dosage form. The residual solvent is removed by drying the dosage form at 40 °C and ambient humidity for 24 hours. The release curve of the finally manufactured dosage form is measured in an aqueous solution of 0.1 N HCl using the USPI paddle method. The finally manufactured dosage form delivers LD and CD at average rates of 17.0 mg / hr and 4.6 mg / hr, respectively, and delivers 85% of LD / CD within 10.0 hours. Figure 9Describes the coincidence release curves of LD and CD. The osmotic delivery system can be retained in the oral cavity until the osmotic layer reaches the delivery orifice, or be retained there for 6 - 7 hours and then swallowed, or be fixed on the teeth that match the oral cavity after combination with the retention platform REP and be retained there for 10 hours.

[0463] Preparation of the controlled - release platform of Example 8

[0464] In this example, the steps of Example 7 were repeated. The dosage form includes the same drug layer, osmotic layer, and coating film as provided in Example 7. In this example, the film weight gain is 4.0%, and the delivery orifice sizes are changed to 0.5 mm, 0.75 mm, and 1.0 mm. The finally manufactured dosage forms deliver LD and CD at average rates of 21.3 mg / hr and 5.7 mg / hr, respectively, and deliver 85% of LD / CD within 8.0 hours. As Figure 10 shown, the delivery orifice size has no significant effect on the release curve. The osmotic delivery system can be retained in the oral cavity until the osmotic layer reaches the delivery orifice, or be retained there for 4 - 5 hours and then swallowed, or be fixed on the teeth that match the oral cavity after combination with the retention platform REP and be retained there for 8 hours.

[0465] Preparation of the controlled - release platform of Example 9

[0466] In this example, the steps of Example 7 were repeated. The dosage form consists of the same drug layer as provided in Example 7, but the osmotic layer contains sodium carboxymethylcellulose 9H4XF instead of 7H4XF. In this example, the film - forming composition and the delivery orifice size are also the same as in Example 6. The weight gain of the coating film of this dosage form is 2.0%. As Figure 11 shown, this dosage form delivers LD and CD at average rates of 24.3 mg / hr and 6.6 mg / hr, respectively, and delivers 85% of LD / CD within 7.0 hours. The osmotic delivery system can be retained in the oral cavity until the osmotic layer reaches the delivery orifice, or be retained there for 3 - 4 hours and then swallowed, or be fixed on the teeth that match the oral cavity after combination with the retention platform REP and be retained there for 7 hours.

[0467] Preparation of the controlled - release platform of Example 10

[0468] In this example, the steps of Example 7 were repeated. The dosage form consists of the same drug layer and osmotic layer as provided in Example 7, and the film - forming composition contains 60 wt% of cellulose acetate with an acetyl content of 39.8% and 40 wt% of copovidone VA 64 by weight percentage. The weight gain of the film of this dosage form is 5.0%. As Figure 12As shown, the dosage form delivered 85% of LD / CD within 6 hours. The osmotic delivery system can remain in the oral cavity until the osmotic layer reaches the delivery orifice, or it can remain there for 2 - 3 hours and then be swallowed, or it can be fixed on the teeth that match the oral cavity after being combined with the retention platform REP and remain there for 6 hours.

[0469] Preparation of the Controlled Release Platform of Example 11

[0470] In this example, the procedure of Example 7 was repeated to provide a dosage form.

[0471] In this example, the drug layer contained 45.0 wt% of LD, 31.0 wt% of hydroxypropylcellulose (Klucel EXF), 16.0 wt% of mannitol, 5.0 wt% of polyvinylpyrrolidone K30, 1.0 wt% of aspartame, 1.0 wt% of mint essence, and 1.0 wt% of magnesium stearate. The osmotic layer contained 55 wt% of sodium carboxymethylcellulose 7H4XF, 34.0 wt% of sorbitol, 10.0 wt% of polyvinylpyrrolidone K30, 0.5 wt% of iron oxide red, and 0.5 wt% of magnesium stearate.

[0472] The drug layer (500 mg) and the osmotic layer granules (250 mg) were compressed into a double - layer tablet core using a 16×7 capsule - shaped mold.

[0473] The double - layer tablet core was coated with a coating film, and the weight gains of the coating film were 4.2 wt%, 6.7 wt%, and 9.7 wt% respectively. The film - forming composition contained 60 wt% of cellulose acetate with an acetyl content of 39.8% and 40 wt% of copolyvidone VA64. An outlet hole of 1.0 mm was mechanically drilled on the drug layer side of the dosage form. The residual solvent was removed by drying the dosage form at 40 °C and ambient humidity for 24 hours.

[0474] As Figure 13 shown, the dosage forms delivering LD at average rates of 38.3 mg / hr, 27.3 mg / hr, and 21.3 mg / hr with film weight gains of 4.2%, 6.7%, and 9.7% respectively delivered 85% of LD within 5.0 hours, 7.0 hours, and 9.0 hours respectively.

[0475] Preparation of the Controlled Release Platform of Example 12

[0476] In this example, the steps of Example 11 were repeated to provide a dosage form except for the film - forming composition. In this example, the double - layer tablet core contained a film - forming composition which contained 70 wt% of cellulose acetate with an acetyl content of 39.8% and 30 wt% of copolyvidone VA64 by weight percentage. The film - forming composition was dissolved in a mixed solvent containing 90% acetone, 9.0% ethanol, and 1.0% deionized water to make a 4% solid solution. As Figure 14As shown, the dosage forms with film weight increases of 4.6 wt% and 7.9 wt% deliver the LD at average rates of 25.5 mg / hr and 16.9 mg / hr, respectively, and 85% of the LD is delivered in 7.5 hours and 11.5 hours, respectively.

[0477] Preparation of the Sustained Release Platform of Example 13

[0478] In this example, the steps of Example 12 were repeated to provide the dosage form. In this example, the dosage forms with film weight gains of 4.8% and 7.7% that had been dried were 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% peppermint flavor (as shown in c of Figure 3). The immediate release overcoat composition was added to ethanol to make a 6.7% solids suspension. The final dosage form comprised an immediate release overcoat layer of 62.5 mg CD and 25 mg LD, and 225 mg LD was contained in the sustained release drug layer. As Figure 15 shown, the release curves of the dosage forms showed rapid release of LD / CD, followed by sustained release for approximately 8.5 hours and 12.0 hours, respectively. The osmotic delivery system with a 4.8% film weight increase could remain in the mouth for 4 - 5 hours and then remain in the mouth during feeding times or throughout the release period. The osmotic delivery system with a 7.7% film weight gain could remain in the mouth for 8 - 9 hours before swallowing, or remain in the mouth throughout the release period, or be fixed to the teeth that coincide with the oral cavity after combination with the retention platform REP and remain there for 12 hours.

[0479] Preparation of the Sustained Release Platform of Example 14

[0480] In this example, the steps of Example 6 were repeated. The dosage form included a drug layer and a film-forming composition similar to those provided in Example 6. The drug layer included 38.0 wt% of levodopa, 50.0 wt% microcrystalline cellulose, 2.0 wt% magnesium stearate, and 10.0 wt% hypromellose, by weight percentage. The coating film included a 50 wt% cellulose acetate membrane with 39.8 wt% acetyl groups, and 50 wt% copovidone VA64. In this example, the film weight increase was 4.50%. The finally manufactured dosage form delivered levodopa at an average rate of 9.4 mg / hr, and 85% of the levodopa was delivered within 9.0 hours.

[0481] Preparation of the Sustained Release Platform of Example 15

[0482] In this example, the steps of Example 6 are repeated. The dosage form includes a drug layer and a film-forming composition similar to those provided in Example 6. The drug-containing layer includes 19.5 wt% of levodopa, 20.0 wt% of carbidopa, 50.0 wt% of mannitol, and 10.0 wt% of citric acid, by weight percentage. The coating film includes a 50 wt% cellulose acetate membrane containing 39.8 wt% acetyl groups, and 50 wt% of copovidone VA64. In this example, the membrane weight gain is 4.50%. The finally manufactured dosage form delivers levodopa at an average rate of 22.9 mg / hr and delivers 85% of levodopa within 13.0 hours.

[0483] Preparation of Sustained Release Platform of Example 16

[0484] In this example, the steps of Example 7 are repeated. The dosage form includes a drug layer, an osmotic layer, and a film-forming composition similar to those in Example 7. The drug layer includes 70.0 wt% of levodopa, 9.0 wt% of mannitol, 20.0 wt% of polyvinylpyrrolidone K30, and 1.0 wt% of magnesium stearate, by weight percentage. The osmotic layer includes 85.0 wt% of sodium carboxymethylcellulose (7H4XF), 3.0 wt% of polyvinylpyrrolidone K30, 5.0 wt% of sorbitol, 5.0 wt% of iron oxide red, and 2.0 wt% of magnesium stearate, by weight percentage. The coating film includes a 70 wt% cellulose acetate membrane containing 39.8 wt% acetyl groups, and 30 wt% of copovidone VA64, by weight percentage. In this example, the membrane weight gain is 4.5%. The finally manufactured dosage form delivers levodopa at an average rate of 35.0 mg / hr and delivers 85% of levodopa within 8.5 hours.

[0485] Preparation of Sustained Release Platform of Example 17

[0486] In this example, the steps of Example 7 are repeated. The dosage form includes a drug layer, an osmotic layer, and a film-forming composition similar to those in Example 7. The drug layer includes 20.0 wt% of levodopa, 20.0 wt% of carbidopa, 50.0 wt% of hydroxypropyl cellulose, 4.0 wt% of mannitol, 5.0 wt% of aspartame, and 1.0 wt% of magnesium stearate, by weight percentage. The osmotic layer includes 25.0 wt% of sodium carboxymethylcellulose (7H4XF), 9.5 wt% of polyvinylpyrrolidone K30, 65.0 wt% of sorbitol, and 0.5 wt% of magnesium stearate, by weight percentage. The coating film includes a 90 wt% cellulose acetate membrane containing 39.8 wt% acetyl groups, and 10 wt% of copovidone VA64, by weight percentage. In this example, the membrane weight gain is 4.5%. The finally manufactured dosage form delivers levodopa and CD at an average rate of 7.1 mg / hr and delivers 85% of levodopa / CD within 12 hours.

[0487] Preparation of Sustained Release Platform in Example 18

[0488] In this example, the steps of Example 13 were repeated. The dosage form includes a drug layer, an osmotic layer, a film-forming composition, and an outer coating similar to those in Example 13. The drug layer includes 45.0 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, by weight percentage. The osmotic layer includes 60.0 wt% sodium carboxymethyl cellulose (7H4XF), 10.0 wt% polyvinylpyrrolidone K30, 26.0 wt% sorbitol, 2.0 wt% iron oxide red, and 2.0 wt% magnesium stearate, by weight percentage. The coating film includes a 70 wt% cellulose acetate film containing 39.8 wt% acetyl groups, and 30 wt% copolyvinylpyrrolidone VA64, by weight percentage. The weight of the coating film is 4.5% of the weight of the tablet core. The rapidly disintegrating outer coating includes 93.0 wt% CD, 2.0 wt% hydroxypropyl cellulose, and 5.0 wt% aspartame, by weight percentage; the weight of the outer coating is 13.2% of the weight of the tablet core (tablet core + first coating film cellulose acetate and copolyvinylpyrrolidone VA64). The rapidly disintegrating outer coating of the dosage form is released rapidly first, and then the release continues for about 8 hours of sustained release. The osmotic delivery system can remain in the oral cavity for 4 - 5 hours, then be swallowed before eating or remain in the oral cavity throughout the release period, or be fixed on the teeth that match the oral cavity after being combined with the retention platform REP and remain there for 8 hours.

[0489] Preparation of Sustained Release Platform in Example 19

[0490] In this example, the steps of Example 13 are repeated. The dosage form includes a drug layer, an osmotic layer, a film-forming composition, and an outer coating similar to those in Example 13. The drug layer includes 45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 12.0 wt% mannitol, 5.0 wt% polyvinylpyrrolidone K30, 5.0 wt% mint essence, 1.0 wt% magnesium stearate, and 1.0 wt% aspartame, by weight percentage. The osmotic layer includes 40.0 wt% sodium carboxymethyl cellulose (7H4XF), 20.0 wt% polyvinylpyrrolidone K30, 36.0 wt% sorbitol, 3.5 wt% iron oxide red, and 0.5 wt% magnesium stearate, by weight percentage. The coating film includes a 70 wt% cellulose acetate membrane containing 39.8 wt% acetyl groups, and 30 wt% copolyvinylpyrrolidone VA64, by weight percentage. The weight of the coating film is 4.5% of the weight of the tablet core. The immediate-release outer coating includes 75.0 wt% LD, 20.0 wt% hydroxypropyl cellulose, and 5.0 wt% mint essence, by weight percentage; the weight of the outer coating is 13.2% of the weight of the tablet core (tablet core + first-layer coating film cellulose acetate and copolyvinylpyrrolidone VA64). The immediate-release outer coating of the dosage form is released rapidly first, and then the controlled release lasts for about 8 hours. The osmotic delivery system can remain in the oral cavity for 4 - 5 hours, then be swallowed before eating or remain in the oral cavity throughout the release period, or be fixed on the teeth that match the oral cavity after being combined with the retention platform REP and remain there for 8 hours.

[0491] Preparation of Controlled-Release Platform of Example 20

[0492] In this example, the steps of Example 8 were repeated. The dosage form includes a drug layer, an osmotic layer, a film-forming composition, and an outer coating similar to those in Example 8. The drug layer includes 45.0 wt% levodopa, 31.0 wt% hydroxypropyl cellulose, 17.0 wt% mannitol, 5.0 wt% polyvinylpyrrolidone K30, 1.0 wt% magnesium stearate, and 1.0 w% aspartame, by weight percentage. The osmotic layer includes 55.0 wt% sodium carboxymethyl cellulose (7H4XF), 10.0 wt% hydroxypropyl cellulose, 34.0 wt% sorbitol, 0.5 wt% iron oxide red, and 0.5 wt% magnesium stearate, by weight percentage. The coating film includes a 70 wt% cellulose acetate membrane containing 39.8 wt% acetyl groups and 30 wt% copovidone VA64, by weight percentage. The weight of the coating film is 5.9% of the weight of the tablet core. The concentration of the immediate-release outer coating solid suspension is 10.0 wt%, which includes 24.0% wt% levodopa, 65.0 wt% carbidopa monohydrate, 10.0 wt% hydroxypropyl cellulose, and 1.0 wt% aspartame, by weight percentage; the weight of the outer coating is 13.2% of the weight of the tablet core (tablet core + the first-layer coating film of cellulose acetate and copovidone VA64). When the coating liquid solvent of the outer coating is absolute ethanol, the content of the carbidopa-related genotoxic impurity hydrazine in the obtained dosage form is 1.7 ppm, and the content of the carbidopa-related impurity dihydroxyphenylacetone (DHPA) is 0.21%. When the coating liquid solvent of the outer coating is purified water, the concentration of the outer coating solid suspension is 10.0 wt%, including 24.0% wt% levodopa, 65.0 wt% carbidopa monohydrate, 10.0 wt% hydroxypropyl cellulose, and 1.0 wt% aspartame, by weight percentage; the content of the carbidopa-related genotoxic impurity hydrazine in the obtained dosage form is 3.8 ppm, and the content of the carbidopa-related impurity DHPA is 0.28%. When the coating liquid solvent of the outer coating is absolute ethanol, the carbidopa-related genotoxic impurity hydrazine and the impurity DHPA in the obtained dosage form are significantly lower than those in the dosage form obtained when the coating liquid solvent of the outer coating is purified water. The immediate-release outer coating of the dosage form is released rapidly first, and then continuously released at a constant rate for about 8 hours. The osmotic delivery system can be retained in the oral cavity for 3 - 5 hours, and then swallowed before eating or retained in the oral cavity during the entire release period.

[0493] Preparation of the controlled-release platform of Example 21 (each tablet contains 62.5 mg CD + 500 mg LD)

[0494] A dosage form designed, formed, and adapted to distribute the beneficial drugs levodopa and carbidopa monohydrate into the oral cavity is prepared as follows: First, a drug layer composition is prepared, which contains 67.9 wt% of LD, 25.1 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 5.0 wt% of polyvinylpyrrolidone K30, and 1.0 wt% of aspartame. These excipients are respectively sieved through a 40-mesh stainless steel sieve, then mixed with pure 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 Φ1.5 mm sieve, and then mixed with 1.0 wt% of magnesium stearate.

[0495] Next, a second composition, namely the osmotic layer, is prepared, which contains 55.0 wt% of sodium carboxymethyl cellulose 7H4XF, 39.0 wt% of sorbitol, 5.0 wt% of polyvinylpyrrolidone K30, and 0.5 wt% of iron oxide red; these components are each sieved through a 40-mesh stainless steel sieve, then mixed with 95% ethanol and granulated until a uniform wet mass is formed; the wet mass is passed through a 4×4 mm sieve and dried at 80 °C for 2 hours; the dried granules are passed through a Φ1.2 mm sieve, and then mixed with 0.5 wt% of magnesium stearate.

[0496] Next, the drug layer and osmotic layer granules are compressed into a double-layer tablet core. First, 700 mg of the drug layer granules are added to the 19×7.5 mm shaped punch of a tableting machine and tamped, then 350 mg of the osmotic layer granules are added to the punch, and the granules of the two layers are compressed into a contact double-layer tablet core by the tableting machine.

[0497] Next, a coating film is wrapped around the double-layer tablet core. The film-forming composition contains 70 wt% of cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% of copolyvinylpyrrolidone VA 64 by weight percentage. The film-forming composition is dissolved in acetone to make a 4% solid solution. Using the process parameters listed in Example 6, the film-forming composition is sprayed onto the double-layer tablet core in a Glatt GC 1 pan coater to form a coating film, and the film weight gain of the coated tablet is 5.0%. Finally, an exit hole of 1.0 mm is mechanically drilled on the drug layer side of the dosage form. Residual solvents are removed by drying the dosage form at 40 °C and ambient humidity for 72 hours. The immediate-release outer coating includes 24.1 wt% of LD, 64.9 wt% of CD, 10.0 wt% of hydroxypropyl cellulose, and 1.0 wt% of aspartame by weight percentage; the weight of the outer coating is 9.4% of the weight of the tablet core (tablet core + first layer of coating film cellulose acetate and copolyvinylpyrrolidone VA64). The immediate-release outer coating of the dosage form is released rapidly first, and then the controlled release lasts for about 16 hours. The osmotic delivery system can remain in the oral cavity for 16 hours, remain in the oral cavity throughout the release period, or be fixed on the teeth that match the oral cavity after being combined with the retention platform REP and remain there for 16 hours.

[0498] Example 22 Preparation of a Controlled Release Platform (Each Tablet Contains 62.5 mg CD + 375 mg LD)

[0499] In this example, the steps of Example 20 were repeated. The dosage form includes a drug layer, an osmotic layer, a film-forming composition, and an outer coating similar to those in Example 20. The drug layer includes 53.5 wt% of LD, 39.5 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 5.0 wt% of polyvinylpyrrolidone K30, 1.0 wt% of aspartame, and 1.0 wt% of magnesium stearate, by weight percentage. The osmotic layer includes 55.0 wt% of sodium carboxymethyl cellulose 7H4XF, 39.0 wt% of sorbitol, 5.0 wt% of polyvinylpyrrolidone K30, 0.5 wt% of iron oxide red, and 0.5 wt% of magnesium stearate, by weight percentage. The coating film includes a 70 wt% cellulose acetate membrane containing 39.8 wt% of acetyl groups, and 30 wt% of copolyvinylpyrrolidone VA64, by weight percentage. The weight of the coating film is 8.0% of the weight of the tablet core. The immediate-release outer coating includes 24.05 wt% of LD, 64.95 wt% of CD, 10.00 wt% of hydroxypropyl cellulose, and 1.0 wt% of aspartame, by weight percentage; the weight of the outer coating is 9.4% of the weight of the tablet core (tablet core + first-layer coating film cellulose acetate and copolyvinylpyrrolidone VA64). The immediate-release outer coating of the dosage form is released rapidly first, followed by a controlled release with a duration of approximately 16 hours. The osmotic delivery system can remain in the oral cavity for 16 hours, remain in the oral cavity throughout the release period, or be fixed on the teeth that match the oral cavity after being combined with the retention platform REP and remain there for 16 hours.

[0500] Example 23 Preparation of a Controlled Release Platform (Each Tablet Contains 50 mg CD + 500 mg LD)

[0501] A dosage form designed, shaped, and adapted to distribute the beneficial drugs levodopa and carbidopa monohydrate into the oral cavity was prepared as follows: First, a drug layer composition was prepared, which contains 62.5 wt% of LD, 31.0 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 4.5 wt% of mannitol, 0.9 wt% of aspartame, 0.1% wt% of mint essence, and 0.5 wt% of magnesium stearate, by weight percentage. It was dry granulated through a 1.2 mm sieve and then mixed with 0.5 wt% of magnesium stearate.

[0502] Next, a second composition, namely the osmotic layer, was prepared, which contains 55.0 wt% of sodium carboxymethyl cellulose 7H4XF, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose, and 0.5 wt% of iron oxide red; these excipients were mixed and then dry granulated through a 1.2 mm sieve and then mixed with 0.5 wt% of magnesium stearate.

[0503] Next, the drug layer and the osmotic layer granules are compressed into a bilayer tablet core. First, 600 mg of the drug layer granules are added to the 19×7.5 mm shaped punch of the tablet press and tamped down, then 300 mg of the osmotic layer granules are added to the punch, and the granules of the two layers are compressed into a contacting bilayer tablet core using the tablet press.

[0504] Next, the bilayer tablet core is coated with a coating film. The film-forming composition contains 70 wt% of cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% of copovidone VA 64 by weight percentage. The film-forming composition is dissolved in acetone to make a 4% solid solution. Using the process parameters listed in Example 6, the film-forming composition is sprayed onto the bilayer tablet core in a Glatt GC 1 pan coater to form a coating film, and the film weight gain of the coated tablet is 6.5%. Finally, an outlet hole with a diameter of 1.0 mm is mechanically drilled on the drug layer side of the dosage form. The immediate-release outer coating includes 62.15 wt% of LD, 26.85 wt% of CD, 10.0 wt% of hydroxypropyl cellulose, 0.9 wt% of aspartame, and 0.1 wt% of mint essence, by weight percentage; the mass of the outer coating is 21.0% of the mass of the tablet core (tablet core + the first layer of coating film of cellulose acetate and copovidone VA64). As Figure 16 shown, the release curve of the dosage form shows a rapid release of LD / CD, followed by a sustained release with a duration of approximately 16 hours. The osmotic delivery system can remain in the oral cavity for 16 hours, remain in the oral cavity throughout the release period, or be fixed on the teeth that match the oral cavity after being combined with the retention platform REP and remain there for 16 hours.

[0505] Preparation of the controlled-release platform of Example 24 (each tablet contains 37.5 mg of CD + 375 mg of LD)

[0506] A dosage form designed, shaped, and adapted to distribute the beneficial drugs levodopa and carbidopa monohydrate into the oral cavity is prepared as follows: First, a drug layer composition is prepared, which contains 46.9 wt% of LD, 31.0 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 20.1 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint essence, and 0.5 wt% of magnesium stearate by weight percentage. It is dry granulated through a 1.2 mm sieve and then mixed with 0.5 wt% of magnesium stearate.

[0507] Next, a second composition, namely the osmotic layer, is prepared, which contains 55.0 wt% of sodium carboxymethyl cellulose 7H4XF, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose, and 0.5 wt% of iron oxide red; these excipients are mixed and then dry granulated through a 1.2 mm sieve, and then mixed with 0.5 wt% of magnesium stearate.

[0508] Next, the drug layer and the osmotic layer granules are compressed into a bilayer tablet core. First, 600 mg of the drug layer granules are added to the 19×7.5 mm special-shaped punch of the tablet press and tamped, then 300 mg of the osmotic layer granules are added to the punch, and the granules of the two layers are compressed into a contacting bilayer tablet core by the tablet press.

[0509] Next, the bilayer tablet core is wrapped with a coating film. The film-forming composition contains 70 wt% of cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% of copovidone VA 64 by weight percentage. The film-forming composition is dissolved in acetone to make a 4% solid solution. Using the process parameters listed in Example 6, the film-forming composition is sprayed onto the bilayer tablet core in a Glatt GC 1 pan coater to form a coating film, and the film weight gain of the coated tablet is 6.5%. Finally, an outlet hole of 1.0 mm is mechanically drilled on the drug layer side of the dosage form. The immediate-release outer coating includes 62.15 wt% of LD, 26.85 wt% of CD, 10.0 wt% of hydroxypropyl cellulose, 0.9 wt% of aspartame, and 0.1 wt% of mint essence, by weight percentage; the mass of the outer coating is 15.7% of the mass of the tablet core (tablet core + the first coating film of cellulose acetate and copovidone VA64). As Figure 17 shown, the release curve 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 remain in the oral cavity for 16 hours, remain in the oral cavity throughout the release period, or be fixed on the teeth that match the oral cavity after being combined with the retention platform REP and remain there for 16 hours.

[0510] Preparation of the controlled-release platform of Example 25 (each tablet contains 37.5 mg of CD + 250 mg of LD)

[0511] First, a drug layer composition is prepared, which contains 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 essence, and 0.5 wt% of magnesium stearate by weight percentage. They are respectively passed through a 40-mesh stainless steel sieve, then granulated by a dry granulation machine to obtain dry granules, and then mixed with 0.5 wt% of magnesium stearate.

[0512] Then, a second composition, namely the osmotic layer, is prepared, which contains 55.0 wt% of sodium carboxymethyl cellulose 7H4XF, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose, and 0.5 wt% of iron oxide red; these components are each passed through a 40-mesh stainless steel sieve, then granulated by a dry granulation machine to obtain dry granules, and then mixed with 0.5 wt% of magnesium stearate.

[0513] Next, the drug layer and the osmotic layer granules are compressed into a bilayer tablet core. First, 417 mg of the drug layer granules are added to the shaped punch of the tablet press with a size of 16*7 mm and tamped, then 208 mg of the osmotic layer granules are added to the punch, and the granules of the two layers are compressed by the tablet press to form a contacting bilayer tablet core.

[0514] Next, the bilayer tablet core is coated with a coating film. The film-forming composition contains 70 wt% of cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% of copovidone VA 64 by weight percentage. The film-forming composition is dissolved in acetone to form a 4% solid solution. Using the process parameters listed in Example 6, the film-forming composition is sprayed onto the bilayer tablet core in a Glatt GC 1 pan coater to form a coating film, and the film weight gain of the coated tablet is 6.5%. Finally, an exit hole with a diameter of 1.0 mm is laser drilled on the drug layer side of the dosage form.

[0515] Next, the dried dosage form with a 6.5% film weight gain is externally coated with an immediate-release composition containing 54.0 wt% of levodopa, 35.0 wt% of carbidopa monohydrate, 10.0 wt% of hydroxypropyl cellulose, 0.9 wt% of aspartame, and 0.1 wt% of peppermint essence. The immediate-release external coating composition is added to absolute ethanol to form a 10.0 wt% solid suspension. The final dosage form contains an immediate-release coating layer of 62.5 mg of levodopa and 37.5 mg of carbidopa, and 187.5 mg of levodopa is contained in the controlled-release drug layer.

[0516] As Figure 18 shown, the release curve of the dosage form shows a rapid release of LD / CD, followed by a controlled release with a duration of approximately 8 hours. The osmotic delivery system can remain in the oral cavity for 4 - 5 hours, and then be swallowed before eating or remain in the oral cavity throughout the release period.

[0517] Preparation of the controlled-release platform of Example 26 (each tablet contains 37.5 mg CD + 150 mg LD)

[0518] In this example, the steps of Example 25 are repeated, and the dosage form includes a drug layer, an osmotic layer, a film-forming composition, and an external coating similar to those in Example 25.

[0519] First, a drug layer composition is prepared, which contains 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 peppermint essence, and 0.5 wt% of magnesium stearate by weight percentage. It is passed through a 40-mesh stainless steel sieve respectively, then granulated by a dry granulation machine to obtain dry granules, and then mixed with 0.5 wt% of magnesium stearate.

[0520] Next, a second composition, i.e., the osmotic layer, was prepared, which contained 55.0 wt% sodium carboxymethyl cellulose 7H4XF, 34.0 wt% sorbitol, 10.0 wt% hydroxypropyl cellulose, and 0.5 wt% iron oxide red; these components were each passed through a 40-mesh stainless steel sieve and then granulated by a dry granulator to obtain dry granules, which were then mixed with 0.5 wt% magnesium stearate.

[0521] Next, the drug layer and osmotic layer granules were compressed into a bilayer tablet core. First, 250 mg of the drug layer granules were added to a 9-mm round punch of a tablet press and tamped, then 125 mg of the osmotic layer granules were added to the punch, and the granules of the two layers were compressed by the tablet press to form a contacting bilayer tablet core.

[0522] Next, the bilayer tablet core was coated with a coating film. The film-forming composition contained 70 wt% cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% copovidone VA 64 by weight percentage. The film-forming composition was dissolved in acetone to form a 4% solid solution. Using the process parameters listed in Example 6, the film-forming composition was sprayed onto the bilayer tablet core in a Glatt GC 1 pan coater to form a coating film, and the film weight gain of the coated tablet was 7.0%. Finally, an exit hole with a diameter of 0.75 mm was laser drilled on the drug layer side of the dosage form.

[0523] Next, the dried dosage form with a 7.0% film weight gain was externally coated with an immediate-release composition containing 42.8 wt% levodopa, 46.2 wt% carbidopa monohydrate, 10.0 wt% hydroxypropyl cellulose, 0.9 wt% aspartame, and 0.1 wt% peppermint essence. The immediate-release external coating composition was added to absolute ethanol to form a 10.0 wt% solid suspension. The final dosage form contained an immediate-release coating layer of 37.5 mg levodopa and 37.5 mg carbidopa, and 112.5 mg levodopa was contained in the controlled-release drug layer.

[0524] As Figure 19 shown, the release curve of the dosage form showed a rapid release of LD / CD, followed by a controlled release with a duration of approximately 8 hours. The osmotic delivery system could remain in the oral cavity for 4 - 5 hours, and then be swallowed before eating or remain in the oral cavity throughout the release period.

[0525] Preparation of the controlled-release platform of Example 27 (each tablet contains 37.5 mg CD + 75 mg LD)

[0526] 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 external coating similar to those in Example 25.

[0527] First, a drug layer composition is prepared, which contains 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 essence, and 0.5 wt% of magnesium stearate. They are respectively passed through a 40-mesh stainless steel sieve and then granulated by a dry granulation machine to obtain dry granules, and then mixed with 0.5 wt% of magnesium stearate.

[0528] Next, a second composition, i.e., the osmotic layer, is prepared, which contains 55.0 wt% of sodium carboxymethyl cellulose 7H4XF, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose, and 0.5 wt% of iron oxide red; these components are respectively passed through a 40-mesh stainless steel sieve and then granulated by a dry granulation machine to obtain dry granules, and then mixed with 0.5 wt% of magnesium stearate.

[0529] Next, the drug layer and osmotic layer granules are pressed into a double-layer tablet core. First, 125 mg of the drug layer granules are added to a 7-mm round punch of a tablet press and tamped, then 62.5 mg of the osmotic layer granules are added to the punch, and the granules of the two layers are pressed by the tablet press to form a contacting double-layer tablet core.

[0530] Next, a coating film is wrapped around the double-layer tablet core. The film-forming composition contains 70 wt% of cellulose acetate with an acetyl content of 39.8 wt% and 30 wt% of copovidone VA 64 by weight percentage. The film-forming composition is dissolved in acetone to make a 4% solid solution. Using the process parameters listed in Example 6, the film-forming composition is sprayed onto the double-layer tablet core in a Glatt GC 1 pan coater to form a coating film, and the film weight gain of the coated tablet is 9.0%. Finally, an exit hole with a diameter of 0.5 mm is laser-drilled on the drug layer side of the dosage form.

[0531] Next, the dried dosage form with a 9.0% film weight gain is externally coated with an immediate-release composition containing 28.2 wt% of levodopa, 60.8 wt% of carbidopa monohydrate, 10.0 wt% of hydroxypropyl cellulose, 0.9 wt% of aspartame, and 0.1 wt% of mint essence. The immediate-release external coating composition is added to absolute ethanol to make a 10.0 wt% solid suspension. The final dosage form contains an immediate-release coating layer of 18.75 mg of levodopa and 37.5 mg of carbidopa, and 56.25 mg of levodopa is contained in the controlled-release drug layer.

[0532] As Figure 20 shown, the release curve 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 retained in the oral cavity for 4 - 5 hours and then swallowed before eating or retained in the oral cavity throughout the release period.

[0533] Example 28: Cooperation between the controlled-release platform and the retention platform

[0534] Fix the controlled-release platform (ERP) of Examples 6 to 27 to the personalized retention platform (REP) of Examples 1 to 5 to form the controlled-release dosage form (ERP+REP) of the present disclosure. Then, fix the controlled-release dosage form (ERP+REP) to the corresponding teeth in the oral cavity. The controlled-release dosage form (ERP+REP) can be retained in the oral cavity until the pushing layer reaches the delivery port, or be retained there for 4 - 24 hours. Remove the controlled-release dosage form (ERP+REP), replace the controlled-release platform (ERP), and refix the controlled-release dosage form (ERP+REP) to the corresponding teeth in the oral cavity to continue drug release.

[0535] Example 29: Preparation of the controlled-release platform and its cooperation with the retention platform (each tablet contains 62.5 mg CD + 250 mg LD)

[0536] Repeat the steps of Example 9 in this example to provide the dosage form. In this example, a dry dosage form with a 4.8% film weight gain is film-coated with an immediate-release composition containing 23.78 wt% LD, 64.22 wt% CD, 10.0 wt% hydroxypropyl cellulose, and 1.0 wt% aspartame (as shown in c of Figure 3). The immediate-release film-coating composition is added to ethanol to make a 6.7% solid suspension. The final controlled-release platform ERP dosage form contains an immediate-release coating layer of 62.5 mg CD and 25 mg LD, and 225 mg LD is contained in the controlled-release drug layer.

[0537] Fix the controlled-release platform (ERP) to the personalized retention platform (REP) to form the controlled-release dosage form (ERP+REP) of the present disclosure. Then, fix the controlled-release dosage form (ERP+REP) to the corresponding teeth in the oral cavity. The controlled-release dosage form (ERP+REP) can be retained in the oral cavity until the pushing layer reaches the delivery port, or be retained there for 8 hours. Remove the controlled-release dosage form (ERP+REP), replace the controlled-release platform (ERP), and refix the controlled-release dosage form (ERP+REP) to the corresponding teeth in the oral cavity to continue drug release.

[0538] Use the USPI basket method to determine the release curve of the controlled-release dosage form (ERP+REP) in 0.1N hydrochloric acid aqueous solution. As Figure 21 shown, the controlled-release dosage form (ERP+REP) with a 4.8% film weight gain delivers LD at an average rate of 27.6 mg / hr, delivers 85% of LD within 7.7 hours, and delivers 85% of CD within 1 hour.

[0539] Although the specific embodiments of the present disclosure have been described above, those skilled in the art should understand that these are only examples. Without departing from the principles and essence of the present disclosure, various changes or modifications can be made to these embodiments. Therefore, the protection scope of the present disclosure is defined by the appended claims.

[0540] Example 30 Cobalt-chromium alloy posterior-inserted oral retention device

[0541] Figure 22 In the illustrated embodiment, the tablet posterior-inserted oral retention device is composed of a tooth-fitting member 11 and a drug-carrying member 41 connected. The tooth-fitting member 11 can be closely fitted with the teeth in the subject's oral cavity, and the size of the drug-carrying member 41 enables it to accommodate at least one tablet and retain the tablet in the oral cavity. Both the tooth-fitting member 11 and the drug-carrying member 41 are prepared from cobalt-chromium alloy, and the tooth-fitting member 11 and the drug-carrying member 41 are connected to each other at their respective sides. The drug-carrying member includes a ring body 31 and a limiting member 21 located at the end. The ring body 31 is a circular closed loop body with an opening 311 for inserting the tablet. The limiting member is spaced from the ring body and is respectively connected to the tooth-fitting member 11; in another solution, the limiting member can be integrally formed with the ring body and then fixed on the tooth-fitting member, or can be integrally formed with the ring body and the tooth-fitting member. After the oral retention device is matched with the teeth in the subject's oral cavity through the tooth-fitting member, the opening 311 opens towards the molar in the horizontal direction formed by the molar and the incisor (the ring body 31 is located on the side closer to the molar in the horizontal direction, that is, the position of the ring body 31 is closer to the molar than the position of the limiting member 21), and the tablet is inserted in the horizontal direction from the molar towards the incisor. The limiting member is in an arc-shaped hollow structure, and its structure is used to limit the tablet in the drug-carrying member. The tooth-fitting member 11 is fitted with the first molar, the second molar and / or the third molar of the mandible in the subject's oral cavity, and wraps the teeth through fitting.

[0542] When wearing the oral retention device of this embodiment loaded with tablets in the oral cavity, even if intense gargling causes the drug rapid-release layer to dissolve quickly, the tablets can be firmly fixed and will not slip out of the device.

[0543] Example 31 Cobalt-chromium alloy anterior-inserted oral retention device

[0544] Figure 23In the illustrated embodiment, the front-inserted oral retention device for tablets is composed of a tooth-engaging member 12 and a drug-carrying member 42 connected together. The tooth-engaging member 12 can fit closely with the teeth in the subject's oral cavity, and the drug-carrying member 42 is sized to accommodate at least one tablet and retain the tablet in the oral cavity. Both the tooth-engaging member 12 and the drug-carrying member 42 are made of cobalt-chromium alloy, and the tooth-engaging member 12 and the drug-carrying member 42 are connected to each other at their respective sides. The drug-carrying member 42 includes a ring body 32 and a limiting member 22 at the end. The ring body 32 is a circular closed ring body with an opening 321 for inserting the tablet. The limiting member is spaced from the ring body and is respectively connected to the tooth-engaging member 12; in another solution, the limiting member can be integrally formed with the ring body and then fixed to the tooth-engaging member, or can be integrally formed with the ring body and the tooth-engaging member. The opening 321 opens towards the incisors in the horizontal direction formed by the molars and incisors (the ring body 32 is located on the incisor side 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 limiting member 22), and the tablet is inserted in the horizontal direction formed by the molars and incisors from the incisors towards the molars. The limiting member is in a circular arc-shaped hollow structure, and the structure of the limiting member is used to limit the tablet in the drug-carrying member. The tooth-engaging member 12 fits with the first molar, second molar and / or third molar of the mandible in the subject's oral cavity and wraps the teeth through fitting.

[0545] When wearing the oral retention device of this embodiment loaded with tablets in the oral cavity, during the rapid dissolution process of the drug rapid-release layer after intense gargling, the tablet may slip out of the device, and may also slip out of the device during the wearing process, but still has a certain value in use.

[0546] Example 32 Preparation of a cobalt-chromium alloy back-inserted oral retention device by 3D printing

[0547] The preparation method of the cobalt-chromium alloy back-inserted oral retention device of this embodiment includes the following steps:

[0548] Step 1: Scan the size data of the tablet through a "3Shape Dental System" scanner. Then, through "SolidWorks" software, design the drug-carrying member capable of loading the drug part, create and save it as a "standard accessory" file. Each time when designing the oral retention device in the "3Shape Dental System" software, add the "standard accessory" and assemble it with the tooth-engaging member into an integrated oral retention device.

[0549] Step 2: Conduct an intraoral scan:

[0550] a. Open the Trios intraoral scanning software;

[0551] b. Create a new patient, create a new case, and confirm;

[0552] c. Select a research model;

[0553] d. Use the Trios intraoral scanner to scan the mandible;

[0554] e. Perform a maxillary scan;

[0555] f. Perform an occlusal relationship scan;

[0556] g. Post-process the file and confirm that the data of all molars and premolars have been scanned completely without defects. The upper and lower tooth occlusion scans are accurate;

[0557] h. Save the file in 3OXZ or STL format.

[0558] Step 3: Device design

[0559] a. Open the 3Shape Dental System software;

[0560] b. Create a new order;

[0561] c. Select the tooth position;

[0562] d. Select the base crown design;

[0563] e. Import the dental scan tooth data (STL file);

[0564] f. Add the "standard attachment" and assemble it with the tooth fitting component into an integrated oral retention device. The opening is in the horizontal direction formed by the molars and incisors and faces the molars, so that the tablet can be inserted in the horizontal direction formed by the molars and incisors and from the molars towards the incisors.

[0565] g. After the design is completed, export the 3OXZ or STL format file.

[0566] Step 4: 3D printing / fitting and polishing.

[0567] a. Input the CAM program;

[0568] b. Open the EOS laser deposition equipment;

[0569] c. Prepare the cobalt-chromium alloy metal powder;

[0570] d. Download the processing program of the product to be produced;

[0571] e. Click to start processing;

[0572] f. After the processing is completed, open the chamber door to vacuum and clean;

[0573] g. Take out the device and perform fitting / sanding and polishing. The device is shown in Figure 1.

[0574] As Figure 22 shown, the cobalt-chromium alloy posterior insertable oral retention device prepared in this embodiment includes a tooth-fitting member 11 and a drug-carrying member; the tooth-fitting member 11 is connected to the drug-carrying member at their respective sides, the tooth-fitting member can be closely fitted with the teeth in the oral cavity, and the drug-carrying member can accommodate at least one tablet and retain the tablet 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, and the active drug is one of levodopa or its esters, carbidopa, baclofen, acyclovir, valacyclovir, ganciclovir, metformin, and gabapentin, or one or two of levodopa or its esters and carbidopa. The cross-sectional shape of the drug-carrying member is a circular closed loop. The drug-carrying member can be a mesh structure or a non-mesh structure. The drug-carrying member includes at least one ring body 31 and at least one limiting member 21 located at the end, and the ring body 31 forms an opening 311 for inserting the tablet. The limiting member is in a circular arc-shaped hollow form. The opening faces the molar in the horizontal direction formed by the molar and the incisor, and the tablet is inserted in the horizontal direction from the molar towards the incisor.

[0575] Preparation of Cobalt-Chromium Alloy Oral Retention Device by Injection Molding in Example 33

[0576] First, prepare a dental plaster model of the patient / volunteer through traditional mold-taking techniques; then, through traditional manual techniques, use dental wax as the material to manually prepare a dental wax model on the plaster model; finally, use cobalt-chromium porcelain alloy as the material to prepare an oral retention device through traditional injection molding techniques.

[0577] Example 34 Cobalt-Chromium Alloy Anterior Insertable Oral Retention Device Prepared by 3D Printing

[0578] As Figure 23 shown, the oral retention device is prepared by the method of Example 32, and only in step 3f, the positions of the ring body and the limiting member of the drug-carrying member are opposite to those in Example 32. The ring body 32 of the drug-carrying member 42 forms an opening 321 for inserting the tablet, and the opening faces the incisor in the horizontal direction formed by the molar and the incisor, and the tablet is inserted in the horizontal direction from the incisor towards the molar. The tablet can be a controlled-release preparation, preferably an osmotic pump tablet.

[0579] Example 35

[0580] This embodiment is an oral drug delivery device covering all the mandibular teeth. As Figure 24 shown, it includes a core component 1 and a fixing device 2. The fixing device 2 is a fixator. The schematic structural diagram of the core component 1 is as Figure 25 shown, the schematic structural diagram of the fixing device 2 is as Figure 26 shown, and the cross-sectional view of the oral drug delivery device is as Figure 27As shown. The lingual side 201 of the fixing device, the buccal side 202 of the fixing device, and the occlusal surface 203 of the fixing device correspondingly fit with the lingual side, buccal side, and occlusal surface of the tooth and wrap around the outer peripheral surface of the tooth; the fixing device 2 simultaneously wraps around the molar anastomosis functional area 11. The core component 1 is composed of the molar anastomosis functional area 11 and the drug-loading functional area 12. The molar anastomosis functional area 11 can be closely fitted with the first and second mandibular premolars and the first and second molars in the subject's oral cavity. The size of the drug-loading functional area 12 enables it to accommodate at least one tablet and fixes the tablet in the oral cavity. The fixing device 2 is closely fitted with all the mandibular teeth of the subject and is closely 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-loading functional area 12 are prepared from cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-loading functional area 12 are connected to each other at their respective sides. The drug-loading 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. 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. A slot is provided at the position of the fixing device 2 corresponding to the drug-loading functional area 12 to achieve detachable fixation of the fixing device 2 and the core component 1. The fixing device 2 is prepared from colorless transparent polyethylene terephthalate and covers all the mandibular teeth, that is, 14 teeth. After the core component 1 and the fixing device 2 are combined, they match the teeth in the subject's oral cavity.

[0581] After the oral medicator of this embodiment is loaded with tablets, it can be firmly worn in the oral cavity, and the tablets are fixed in the oral cavity. Moreover, the fixator, the core component, and the tablets will not fall off or shift with the oral movements, and the wearing comfort level is high, and the influence on the facial appearance is small.

[0582] Example 36

[0583] This embodiment is an oral medicator covering 10 mandibular teeth, such as Figure 28As shown, it includes a core component 1 and a fixing device 2. The fixing device 2 is a fixator. The core component 1 is composed of a molar anastomosis functional area 11 and a drug-loading functional area 12. The molar anastomosis functional area 11 can be closely fitted with the first and second premolars and the first and second molars of the mandible in the subject's oral cavity. The size of the drug-loading functional area 12 enables it to accommodate at least one tablet and fix the tablet in the oral cavity. The fixing device 2 is closely fitted with a part of the subject's mandibular teeth (including the teeth from the left canine to the right second molar), and is closely 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-loading functional area 12 are prepared from cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-loading functional area 12 are connected to each other at their respective sides. The drug-loading functional area 12 includes a first ring 121 and a second ring 122. The first ring 121 and the second ring 122 are oval closed rings. Along the direction of the open end of the molar anastomosis functional area on the first ring 121, a pair of clamping walls 123 are symmetrically arranged, which are suitable for the insertion of non-cylindrical tablets. The tablets are inserted from the second ring 122 and 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. A slot is provided at the position of the fixing device 2 corresponding to the drug-loading functional area 12 to achieve the detachable fixation of the fixing device 2 and the core component 1. The fixing device 2 is prepared from colorless and transparent polyethylene terephthalate and covers 10 teeth of the mandible from the left canine to the right second molar. After the core component 1 and the fixing device 2 are combined, they match a part of the mandibular teeth in the subject's oral cavity.

[0584] After loading the tablets, the oral drug delivery device of this embodiment can be firmly worn in the oral cavity, fix the tablets in the oral cavity, and neither the fixator, the core component nor the tablets will fall off or shift with the oral movements. It has a high degree of wearing comfort and little impact on the facial appearance.

[0585] Example 37

[0586] This embodiment is an oral drug delivery device covering 7 mandibular teeth, as Figure 29As shown, it includes a core component 1 and a fixing device 2. The fixing device 2 is a fixator. The core component 1 is composed of a molar anastomosis functional area 11 and a drug-loading functional area 12. The molar anastomosis functional area 11 can be closely fitted with the first and second premolars and the first and second molars in the subject's oral cavity. The size of the drug-loading functional area 12 enables it to accommodate at least one tablet and fixes the tablet in the oral cavity. The fixing device 2 is closely fitted with a part of the subject's mandibular teeth (including a total of 7 teeth from the right incisor to the right second molar), and is closely 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-loading functional area 12 are prepared from cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-loading functional area 12 are connected to each other at their respective sides. The drug-loading 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, suitable for inserting a cylindrical tablet. The tablet is inserted from the second ring 122 and 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. A slot is provided at the position of the fixing device 2 corresponding to the drug-loading functional area 12 to achieve detachable fixation of the fixing device 2 and the core component 1. The fixing device 2 is prepared from colorless transparent ethylene-vinyl acetate copolymer and covers a total of 7 teeth from the incisor to the second molar on the right side of the mandible. After the core component 1 and the fixing device 2 are combined, they match the subject's teeth.

[0587] When wearing the oral drug delivery device of this embodiment in the oral cavity, after loading the tablet, the tablet can be fixed in the oral cavity and is not easy to fall off. The wearing firmness has no obvious difference from that of Embodiments 35 and 36. At the same time, because the number of covered teeth is small, its wearing comfort and the influence degree on the facial appearance are better than those of Embodiments 35 and 36.

[0588] Embodiment 38

[0589] The difference between this embodiment and Embodiment 35 is that the oral drug delivery device covers all the upper jaw teeth, and the molar anastomosis functional area 11 can be closely fitted with the second premolar and the first, second, and third molars in the subject's oral cavity, and the rest are the same as Embodiment 35.

[0590] After loading the tablet, the oral drug delivery device of this embodiment can be firmly worn in the oral cavity, and the tablet is fixed in the oral cavity. Moreover, the fixator, the core component, and the tablet will not fall off or shift with the oral movements. The wearing comfort level is high, and the influence degree on the facial appearance is small.

[0591] Embodiment 39

[0592] The difference between this embodiment and Embodiment 35 is that the length of the core component 1 is 3 teeth, which can be designed for subjects with molar defects; the first ring 121 and the second ring 122 are polygonal closed loops, and the molar anastomosis functional area 11 and the fixing device 2 are combined by an adhesive bonding method using pressure-sensitive adhesive. The bonding position is the entire outer surface of the molar anastomosis functional area 11, and the thickness of the adhesive is 0.1 mm; the fixing device 2 is prepared from colorless and transparent ethylene-vinyl acetate copolymer; the rest are the same as Embodiment 35.

[0593] After the oral medicator of this embodiment is loaded with tablets, it can be firmly worn in the oral cavity, and the tablets can be fixed in the oral cavity. Moreover, the fixator, the core component, and the tablets will not fall off or shift with oral movements, and the wearing comfort level is high, and the impact on the facial appearance is small.

[0594] Embodiment 40

[0595] The structural schematic diagram of the oral medicator of this embodiment is as Figure 30 shown, and it includes a core component 1 and a fixing device 2. The fixing device 2 is a fixing layer. The sectional view of the oral medicator is as Figure 31 shown. The core component 1 is composed of a molar anastomosis functional area 11 and a drug-loading functional area 12. The molar anastomosis functional area 11 can be closely fitted with the first and second premolars and the first and second molars in the subject's oral cavity. The drug-loading functional area includes a first ring 121 and a second ring 122. The first ring 121 and the second ring 122 are circular closed loops, which are suitable for inserting cylindrical tablets. The tablets are inserted from the second ring 122 and blocked by the first ring 121. The size of the drug-loading functional area 12 enables it to accommodate at least one tablet and fix the tablets in the oral cavity. The fixing device 2 is attached to the entire outer surfaces of the first section and the second section of the U-shaped structure; the molar anastomosis functional area 11 and the drug-loading functional area 12 are prepared from cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-loading functional area 12 are connected to each other at their respective sides. The fixing device 2 is colorless and transparent polyethylene terephthalate, which is softened by heating and then covered on the surface of the molar anastomosis functional area 11, and the excess material is trimmed after cooling. The thickness of the fixing device 2 is 0.3 - 0.5 mm, and the combination of the core component 1 and the fixing device 2 matches the subject's teeth.

[0596] After the oral medicator of this embodiment is loaded with tablets, it can be firmly worn in the oral cavity, and the tablets can be fixed in the oral cavity. Moreover, the fixing layer, the core component, and the tablets will not fall off or shift with oral movements, and the wearing comfort level is high, and the impact on the facial appearance is small.

[0597] Embodiment 41

[0598] The difference between this embodiment and Embodiment 40 is that the fixing device 2 is made of light blue polycaprolactone, and the thickness of the fixing device 2 is 0.8 - 1 mm, and the rest are the same as those in Embodiment 40.

[0599] After loading the tablet, the oral medicator of this embodiment can be worn stably in the oral cavity and fix the tablet in the oral cavity. However, because the thickness of the fixing device is relatively thick, the wearing firmness and comfort level of the oral medicator in this embodiment are not as good as those in Embodiment 40, and compared with Embodiment 40, the influence degree on the facial appearance in this embodiment is greater.

[0600] Embodiment 42

[0601] The difference between this embodiment and Embodiment 40 is that the core component 1 and the fixing device 2 are combined in a bonding manner with a pressure - sensitive adhesive. The bonding position is the part where the molar anastomosis 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 are the same as those in Embodiment 40.

[0602] After loading the tablet, the oral medicator of this embodiment can be worn stably in the oral cavity and fix the tablet in the oral cavity. However, because the thickness of the fixing layer is relatively thin and the surface of the fixing layer material is relatively smooth, the wearing firmness and comfort level of the oral medicator in this embodiment are not as good as those in Embodiments 40 and 41.

[0603] Embodiment 43

[0604] The oral medicator of this embodiment is as Figure 32As shown in the figure, it includes a core component 1 and a fixing device 2 that are symmetric on the left and right sides. The fixing device 2 is a fixator. The two core components 1 are composed of a molar anastomosis functional area 11 and a drug-loading functional area 12. The molar anastomosis functional area 11 can be closely fitted with the first and second premolars and the first and second molars of the upper jaw in the subject's oral cavity. The size of the drug-loading functional area 12 enables it to accommodate at least one tablet and fixes the tablet in the oral cavity. The fixing device 2 is closely fitted with all the upper teeth of the subject and is also closely 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-loading functional area 12 are prepared from cobalt-chromium alloy, and the molar anastomosis functional area 11 and the drug-loading functional area 12 are connected to each other at their respective sides. The drug-loading 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 loops, suitable for inserting a cylindrical tablet. The tablet is inserted from the second ring 122 and 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. A slot is provided at the position of the fixing device 2 corresponding to the drug-loading functional area 12 to achieve detachable fixation of the fixing device 2 and the core component 1. The fixing device 2 is prepared from colorless and transparent polyethylene terephthalate and covers all the upper teeth. After the core component 1 and the fixing device 2 are combined, they match the teeth in the subject's oral cavity.

[0605] After being loaded with tablets, the oral drug delivery device of this embodiment can be firmly worn in the oral cavity, fix the tablets in the oral cavity, and neither the fixator, the core component nor the tablets will fall off or shift with the oral movements. It has a high level of wearing comfort and little impact on the facial appearance.

[0606] Example 44

[0607] The cobalt-chromium alloy core component is prepared by laser melting and casting, and the fixator is prepared by thermoforming. The specific steps are as follows:

[0608] Step 1: Obtain the subject's oral cavity data by scanning the subject's oral cavity or scanning the plaster model made from an oral impression.

[0609] Step 2: Use 3D design software and dental design software to design the drug-loading functional area and the molar anastomosis functional area of the core component respectively, and combine them in the dental design software to generate the core component design file.

[0610] Step 3: Prepare the cobalt-chromium alloy core component by laser melting and casting, grinding, polishing and cleaning.

[0611] Step 4: Wear the core component on the subject's dental model. Heat and soften the polyethylene terephthalate through a thermoforming machine, evacuate the air on the dental model, trim off the excess material and polish it, and then remove it from the dental model to obtain the oral drug delivery device, which matches the subject's teeth.

[0612] Example 45

[0613] The cobalt-chromium alloy core component is prepared by injection molding and the drug delivery device is prepared by the pressure membrane method. The specific steps are as follows:

[0614] Step 1: Take an oral mold of the subject to make a plaster model.

[0615] Step 2: Use dental wax as the material to prepare a dental wax model on the plaster model.

[0616] Step 3: Use cobalt-chromium porcelain alloy as the material to prepare the core component by traditional injection molding process.

[0617] Step 4: Wear the core component on the plaster dental model. Heat and soften the polyurethane through a pressure membrane machine, evacuate the air on the dental model, trim and polish the excess material, and then remove it from the dental model to obtain the oral drug delivery device composed of the core component and the retainer.

[0618] Example 46

[0619] The cobalt-chromium alloy core component is prepared by injection molding and the drug delivery device is prepared by the impression method. The specific steps are as follows:

[0620] Step 1: Take an oral mold of the subject to make a plaster model.

[0621] Step 2: Use dental wax as the material to prepare a dental wax model on the plaster model.

[0622] Step 3: Use cobalt-chromium porcelain alloy as the material to prepare the drug delivery device by traditional injection molding process.

[0623] Step 4: Wear the core component on the corresponding teeth of the subject. Heat and soften the polycaprolactone material, cover it on the molar anastomosis functional area of the subject's teeth and the core component, and then remove it from the teeth together with the core component after cooling to obtain the oral drug delivery device.

[0624] Comparative Example 1

[0625] The oral drug delivery device of this comparative example only includes the core component 1 in Example 35, as Figure 25 shown.

[0626] Effect Example 1

[0627] 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 shown in Table 2: 1 point was not firm, and the applicator was very easy to fall off under basic oral movements such as opening the mouth and talking after being worn; 2 points were relatively loose, and the applicator sometimes became loose, tilted or fell off under basic oral movements such as opening the mouth and talking after being worn; 3 points were basically firm, and the applicator was easy to fall off only during large-scale oral movements; 4 points were firm, and the applicator only tilted or loosened during large-scale oral movements, but did not fall off; 5 points were very firm, and there was no looseness, tilting or falling off during basic or large-scale oral movements.

[0628] Table 2

[0629] Subjects Example 35 Example 37 Example 40 Comparative Example 1 1 5 5 4 3 2 5 5 5 5 3 5 5 5 4 4 5 5 5 3 5 5 5 4 2

[0630] 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 compared with the comparative example 1 which only uses a core component, the wearing firmness is better, and the wearing firmness of the fixing device using a fixer is higher than that of the fixing layer.

[0631] Effect Example 2

[0632] The wearing comfort test was conducted on the oral applicators of Example 35, Example 37, Example 40 and Comparative Example 1, and the wearing comfort scores were as shown in Table 3 below: 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 quite 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.

[0633] Table 3

[0634] Subjects Example 35 Example 37 Example 40 Comparative Example 1 1 3 4 4 3 2 4 5 5 5 3 3 4 4 3 4 4 5 4 3 5 3 4 4 2

[0635] It can be seen from Table 3 that Examples 35, 37 and 40 of the present application, which combine the fixing device and the core component, are more comfortable to wear than Comparative Example 1 which only uses the core component.

[0636] Effect Example 3

[0637] 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: 1 point means the influence on facial appearance is the greatest and unacceptable; 2 points means the influence on facial appearance is relatively large and not quite acceptable; 3 points means the influence on facial appearance is acceptable but acceptable; 4 points means the influence on facial appearance is small; 5 points means there is almost no difference in facial appearance before and after wearing.

[0638] Table 4

[0639] Subjects Example 35 Example 37 Example 40 Comparative Example 1 1 4 5 5 5 2 5 5 5 5 3 4 4 4 4 4 4 4 4 4 5 4 4 4 4

[0640] As can be seen from Table 4 above, in Example 35, Example 37, and Example 40 of the present application, the method of combining the fixing device and the core component is adopted. Compared with Comparative Example 1 that only uses the core component, the degree of influence on the facial appearance when wearing the oral medicator is close, that is, the oral medicator of the embodiment of the present application has a similar wearing aesthetics compared with the comparative example.

[0641] For the coating film involved in the following examples and comparative examples, the tensile strength is about 1-10 Mpa; the elongation at break is about 1.1-2.0; the average thickness is about 100±8 μm to 200±10 μm. Hydroxypropyl cellulose with a weight average molecular weight of 80,000 can be Hydroxypropyl cellulose EXF, and its Brookfield viscosity is about 300-600 mPa·s, and the concentration is about 10%.

[0642] Preparation of the osmotic pump tablet of Example 47

[0643] The osmotic pump tablet of this example uses levodopa as the drug active ingredient and is prepared according to the following steps:

[0644] (1) Preparation of the drug-containing layer

[0645] Based on the total weight of the drug-containing layer, take 63.0 wt% of levodopa, 10.0 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 5.0 wt% of polyvinylpyrrolidone (K29 / 32), 10.0 wt% of poloxamer (P407), 10.0 wt% of sorbitol, 0.9 wt% of aspartame, 0.1 wt% of mint essence, and 0.5 wt% of magnesium stearate. The above components are each passed through a 40-mesh stainless steel sieve, and then dry granulated; sized through a 1.2-mm stainless steel sieve, and then mixed with 0.5 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0646] (2) Preparation of the boosting layer

[0647] Based on the total weight of the boosting layer, take 49.0 wt% of sodium carboxymethylcellulose (7H4XF), 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF), and 0.5 wt% of iron oxide red; the above components are each passed through a 40-mesh stainless steel sieve, and then dry granulated; sized through a 1.2-mm stainless steel sieve, and then mixed with 0.5 wt% of magnesium stearate to obtain the boosting layer granules.

[0648] (3) Preparation of the double-layer tablet core

[0649] The drug-containing layer granules and the booster layer granules are compressed into a double-layer tablet core, and the tableting punch die is a 21*9.5 mm capsule-shaped punch. 1047.6 mg of the drug-containing layer granules are added to the tableting machine punch and tamped, and then 360 mg of the booster layer granules are added to the punch, and the granules of the two layers are compressed by the tableting machine into a contact double-layer tablet core. The final double-layer tablet core contains about 660 mg of levodopa.

[0650] (4) Preparation of osmotic pump tablets

[0651] The double-layer tablet core is wrapped with a coating film. The raw material composition of the coating film includes 55 wt% cellulose acetate and 45 wt% copovidone VA64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% acetyl group. This composition is dissolved in acetone to make a 4% solution. The solution is sprayed onto the double-layer tablet core in a pan coater to form a coating film, and an osmotic pump tablet is obtained. Based on the obtained double-layer osmotic pump tablet, the coating film content is 6.5 wt%. A 1.0 mm drug release hole is drilled in the coating film with a laser or mechanically.

[0652] The release curve of the finally manufactured dosage form is measured in simulated saliva using the USPI paddle method. Figure 33 The release curve of LD is described. The osmotic pump tablet of this example can be held in the oral cavity, so that the release duration of 85% of the active drug in the osmotic pump tablet is about 8 hours, and the drug released in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0653] Preparation of osmotic pump tablet of Example 48

[0654] In this example, the operations of Example 47 are repeated, with the differences being:

[0655] (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 punch die is a 21*12 mm capsule-shaped punch.

[0656] (2) The coating film includes 50 wt% cellulose acetate membrane and 50 wt% copovidone VA64. Based on the obtained osmotic pump tablet, the content of the coating film is 6.0 wt%.

[0657] The release curve of the finally manufactured dosage form is measured in simulated saliva using the USPI paddle method. Figure 34 The release curve of LD is described. The osmotic pump tablet of this example can be held in the oral cavity, so that the release duration of 85% of the active drug in the osmotic pump tablet is about 8 hours, and the drug released in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0658] Preparation of Osmotic Pump Tablets in Example 49;

[0659] The osmotic pump tablets of this example use levodopa as the drug active ingredient. In this example, the operations of Example 47 are repeated, with the differences being:

[0660] (1) Preparation of the drug-containing layer

[0661] Based on the total mass of the drug-containing layer, take 58.0 wt% of levodopa, 15.0 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 5.0 wt% of polyvinylpyrrolidone (K29 / 32), 5.0 wt% of poloxamer (P407), 15.0 wt% of sorbitol, 0.9 wt% of aspartame, and 0.1 wt% of mint essence. The above components are each passed through a 40-mesh stainless steel sieve, then wet granulated and dried in a fluidized bed; sized through a 1.2-mm stainless steel sieve, and then mixed with 1.0 wt% of magnesium stearate to obtain drug-containing layer granules.

[0662] (2) Preparation of the boosting layer

[0663] Based on the total weight of the boosting layer, take 68.5 wt% of sodium carboxymethyl cellulose (7H4XF), 10.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF), and 0.5 wt% of iron oxide red; the above components are each passed through a 40-mesh stainless steel sieve, then dry granulated; sized through a 1.2-mm stainless steel sieve, and then mixed with 0.5 wt% of colloidal silica and 0.5 wt% of magnesium stearate to obtain boosting layer granules.

[0664] (3) Preparation of the double-layer tablet core and osmotic pump tablets

[0665] The weight of the drug-containing layer is 1484.1 mg, the weight of the boosting layer is 510 mg, and the tablet pressing die is a 21*12 mm capsule-shaped punch. The coating film includes 60 wt% of cellulose acetate membrane and 40 wt% of copovidone VA64. Based on the obtained double-layer osmotic pump tablets, the coating film content is 6.5 wt%.

[0666] The release curve of the finally manufactured dosage form is measured in simulated saliva using the USPI paddle method. The osmotic pump tablets are fixed on the teeth that fit the oral cavity after being combined with the oral retention device of Example 30. Figure 35 The release curve of LD is described. The release duration of 85% of the active drug in the osmotic pump tablets is approximately 16 hours. And the drug released in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0667] Preparation of Osmotic Pump Tablets in Example 50

[0668] This example is prepared according to the following steps:

[0669] (1) Preparation of the drug-containing layer

[0670] Based on the total weight of the drug-containing layer, take 58.0 wt% of levodopa, 15.0 wt% of hydroxypropyl cellulose with a weight average molecular weight of 80,000, 5.0 wt% of polyvinylpyrrolidone (K29 / 32), 5.0 wt% of poloxamer (P407), 15.0 wt% of sorbitol, 0.9 wt% of aspartame, and 0.1 wt% of mint essence. The above components are each passed through a 40-mesh stainless steel sieve, then wet granulated and dried in a fluidized bed; sized through a 1.2-mm stainless steel sieve, and then mixed with 1.0 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0671] (2) Preparation of the boosting layer

[0672] Based on the total weight of the boosting layer, take 68.5 wt% of sodium carboxymethyl cellulose (7H4XF), 10.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF), and 0.5 wt% of iron oxide red; the above components are each passed through a 40-mesh stainless steel sieve, then dry granulated; sized through a 1.2-mm stainless steel sieve, and then mixed with 0.5 wt% of colloidal silica and 0.5 wt% of magnesium stearate to obtain the boosting layer granules.

[0673] (3) Preparation of the double-layer tablet core

[0674] Press the drug-containing layer and boosting layer granules into a double-layer tablet core, and the tablet pressing die is a 7.5-mm round punch. Add 758.6 mg of the drug-containing layer granules to the tablet press punch and tamp them, then add 379.3 mg of the boosting layer granules to the punch, and press the two layers of granules with a tablet press to form a contact double-layer tablet core. The final double-layer tablet core contains 440 mg of levodopa.

[0675] (4) Preparation of the osmotic pump tablet

[0676] Wrap the double-layer tablet core with a coating film. The raw material composition of the coating film contains 50 wt% of cellulose acetate, 5 wt% of polyethylene glycol 400, and 45 wt% of copolyvidone VA64 by weight percentage, wherein the cellulose acetate is a cellulose acetate membrane containing 39.8 wt% of acetyl groups. Dissolve the coating film raw material composition in acetone to make a 4% solution. Spray this solution onto the double-layer tablet core in a pan coater to form a coating film to obtain the osmotic pump tablet. Based on the obtained osmotic pump tablet, the coating film content is 4.5 wt%. Drill a 1.0-mm drug release hole in the coating film with a laser or mechanically.

[0677] Measure the release curve of the finally manufactured dosage form in simulated saliva using the USPI paddle method. Figure 36The release curve of LD is described. The osmotic pump tablets of this example can be retained in the oral cavity. The release duration of 85% of the active drug in the osmotic pump tablets is about 5 hours, and the released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0678] Preparation of the osmotic pump tablets of Example 51;

[0679] In this example, the operation of Example 50 was repeated, except that: the weight of the drug-containing layer was 569.2 mg, the weight of the boosting layer was 284.6 mg, and the tablet pressing die was a 7 mm round punch. Based on the obtained bilayer osmotic pump tablets, the coating film content was 6.0 wt%.

[0680] The release curve of the finally manufactured dosage form was measured in simulated saliva using the USPI paddle method. The osmotic pump tablets were fixed on the teeth that fit the oral cavity after being combined with the oral retention device of Example 30. Figure 37 The release curve of LD is described. The release duration of 85% of the active drug in the osmotic pump tablets is about 5 hours. And the released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0681] Preparation of the osmotic pump tablets of Example 52

[0682] In this example, the operation of Example 50 was repeated, except that: the weight of the drug-containing layer was 379.3 mg, the weight of the boosting layer was 189.7 mg, and the tablet pressing die was a 6 mm round punch. Based on the obtained bilayer osmotic pump tablets, the coating film content was 9.0 wt%.

[0683] The release curve of the finally manufactured dosage form was measured in simulated saliva using the USPI paddle method. Figure 38 The release curve of LD is described. The osmotic pump tablets were fixed on the teeth that fit the oral cavity after being combined with the oral retention device of Example 30. The release duration of 85% of the active drug in the osmotic pump tablets is about 5 hours. And the released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0684] Preparation of the osmotic pump tablets of Example 53;

[0685] The osmotic pump tablets of this example were prepared according to the following steps:

[0686] (1) Preparation of the drug-containing layer

[0687] Based on the total weight of the drug-containing layer, take 58.0 wt% of levodopa, 15.0 wt% of hydroxypropyl cellulose with a weight-average molecular weight of 80,000, 5.0 wt% of polyvinylpyrrolidone (K29 / 32), 5.0 wt% of poloxamer (P407), 15.0 wt% of sorbitol, 0.9 wt% of aspartame, and 0.1 wt% of mint essence. The above components are each passed through a 40-mesh stainless steel sieve, then granulated by the wet method, and dried in a fluidized bed; sized through a 1.2-mm stainless steel sieve, and then mixed with 1.0 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0688] (2) Prepare the boosting layer

[0689] Based on the total weight of the boosting layer, take 68.5 wt% of sodium carboxymethyl cellulose (7H4XF), 10.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF), and 0.5 wt% of iron oxide red; the above components are each passed through a 40-mesh stainless steel sieve, and then granulated by the dry method; sized through a 1.2-mm stainless steel sieve, and then mixed with 0.5 wt% of colloidal silicon dioxide and 0.5 wt% of magnesium stearate to obtain the boosting layer granules.

[0690] (3) Prepare the three-layer tablet core

[0691] Press the drug-containing layer granules, the barrier layer material, and the boosting layer granules into a three-layer tablet core, and the tablet pressing die is a 7.5-mm round punch. Add 758.6 mg of the drug-containing layer granules to the tablet press punch and tamp them, then add 50 mg of the barrier layer material ethyl cellulose N10 to the punch and tamp it, and finally add 379.3 mg of the boosting layer granules to the punch, and press them into a contact three-layer tablet core with a tablet press. The final three-layer tablet core contains approximately 440 mg of levodopa.

[0692] (4) Prepare the osmotic pump tablet

[0693] Wrap the three-layer tablet core with a coating film. The coating film raw material composition contains 50 wt% of cellulose acetate, 5 wt% of polyethylene glycol 400, and 45 wt% of copolyvinylpyrrolidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. Dissolve the coating film raw material composition in acetone to make a solution with a solid content of 4%. Spray the solution onto the three-layer tablet core in a pan coater to form a coating film to obtain the osmotic pump tablet. Based on the obtained osmotic pump tablet, the coating film content is 4.5 wt%. Drill a 1.0-mm drug release hole in the coating film with a laser or mechanically.

[0694] The release profile of the finally manufactured dosage form was measured in simulated saliva using the USPI paddle method. The osmotic pump tablets of this example can be retained in the oral cavity. The release duration of 85% of the active drug in the osmotic pump tablets is approximately 5 hours, and the released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0695] Preparation of Osmotic Pump Tablets in Example 54

[0696] An osmotic pump tablet designed, shaped and adapted to be used in conjunction with Example 30, containing levodopa and carbidopa monohydrate, was prepared as follows:

[0697] (1) Prepare the drug-containing layer, which consists of two parts. Based on the total weight of the drug-containing layer, the first part contains 54.9 wt% levodopa, 15.0 wt% hydroxypropyl cellulose with a weight average molecular weight of 80,000, 5.0 wt% polyvinylpyrrolidone (K29 / 32), 3.07 wt% sorbitol and 0.9 wt% aspartame. Each is sieved through a 40-mesh stainless steel sieve, then granulated by wet method and dried in a fluidized bed; sized through a 1.2-mm stainless steel sieve. The second part contains 3.16 wt% carbidopa monohydrate, 11.8 wt% sorbitol and 5.0 wt% poloxamer (P407). Each is sieved through a 40-mesh stainless steel sieve, then granulated by hot melt method and sized through a 1.2-mm stainless steel sieve. After mixing the first part and the second part of the granules, an additional 0.1 wt% mint essence, 0.1 wt% dibutylhydroxytoluene and 1.0 wt% magnesium stearate are mixed to obtain the drug-containing layer granules.

[0698] (2) Prepare the boosting layer

[0699] Based on the total weight of the boosting layer, take 68.5 wt% sodium carboxymethylcellulose (7H4XF), 10.0 wt% sorbitol, 20.0 wt% hydroxypropyl cellulose (EXF) and 0.5 wt% iron oxide red; each is sieved through a 40-mesh stainless steel sieve, then granulated by dry method; sized through a 1.2-mm stainless steel sieve, and then mixed with 0.5 wt% colloidal silica and 0.5 wt% magnesium stearate to obtain the boosting layer granules.

[0700] (3) Prepare the double-layer tablet core

[0701] Press the drug-containing layer granules and the boosting layer granules into a double-layer chip. The tablet pressing die is a 7.0-mm round punch. Add 563.9 mg of the drug-containing layer granules to the tablet press punch and tamp them, then add 282.0 mg of the boosting layer granules to the punch, and press the granules of the two layers with a tablet press to form a contact double-layer tablet core. The final double-layer tablet core contains 309.4 mg of levodopa and 16.5 mg of carbidopa.

[0702] (4) Preparation of osmotic pump tablets

[0703] Wrap the double-layer tablet core with a coating film. The raw material composition of the coating film contains 50 wt% cellulose acetate with an acetyl content of 39.8 wt%, 5 wt% polyethylene glycol 400, and 45 wt% copovidone VA 64 by weight percentage. Dissolve this raw material composition in acetone to make a 4% solution. Spray this solution onto the double-layer tablet core in a pan coater to form a coating film, obtaining the osmotic pump tablets. Based on the obtained osmotic pump tablets, the coating film content is 7.0 wt%. Drill a 1.0 mm drug release hole in the coating film with a laser or mechanically.

[0704] (5) Preparation of outer coating

[0705] The raw material composition of the outer coating includes 49.2 wt% levodopa, 28.3 wt% carbidopa, 20.0 wt% hydroxypropyl cellulose, 1.47 wt% dibutylhydroxytoluene, and 1.0% triethyl citrate. These components are made into a 10 wt% solution in ethanol, and the solution is sprayed onto the osmotic pump tablets in a pan coater. The outer coating layer contains 18.75 mg of levodopa and 10.8 mg of carbidopa.

[0706] The double-layer osmotic pump tablets of this example can be held in the oral cavity. The release duration of about 85% of the active drug in the osmotic pump tablets is approximately 8 hours, and the released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0707] Preparation of osmotic pump tablets in Example 55

[0708] An osmotic pump tablet designed, shaped, and adapted to be used in conjunction with Example 30, the osmotic pump tablet containing the active drugs levodopa and carbidopa monohydrate, is prepared according to the following steps:

[0709] (1) Preparation of the drug-containing layer, which consists of two parts. Based on the total weight of the drug-containing layer, the first part contains 54.9 wt% levodopa, 15.0 wt% hydroxypropyl cellulose with a weight average molecular weight of 80,000, 8.07 wt% mannitol, and 0.9 wt% aspartame. Each is sieved through a 40-mesh stainless steel sieve, then wet granulated and dried in a fluidized bed; sized through a 1.2 mm stainless steel sieve. The second part contains 3.16 wt% carbidopa monohydrate, 11.8 wt% mannitol, and 5.0 wt% poloxamer (P407). Each is sieved through a 40-mesh stainless steel sieve, then melt granulated and sized through a 1.2 mm stainless steel sieve. After mixing the first part and the second part of the granules, additionally mix 0.1% wt peppermint essence, 0.1% wt dibutylhydroxytoluene, and 1.0% wt magnesium stearate to obtain the drug-containing layer granules.

[0710] (2) Preparation of the boosting layer

[0711] Based on the total weight of the boosting layer, take 68.5 wt% sodium carboxymethylcellulose (7H4XF), 10.0 wt% sorbitol, 20.0 wt% hydroxypropyl cellulose (EXF), and 0.5 wt% iron oxide red; each of these components is passed through a 40-mesh stainless steel sieve, and then dry granulated; sorted through a 1.2-mm stainless steel sieve, and then mixed with 0.5 wt% colloidal silica and 0.5 wt% magnesium stearate to obtain the boosting layer granules.

[0712] (3) Preparation of the double-layer tablet core

[0713] Press the drug-containing layer granules and the boosting layer granules into a double-layer chip, and the tablet punching die is a 7.0-mm round punch. Add 563.9 mg of the drug layer granules into the punch of the tablet press and tamp them, then add 282.0 mg of the osmotic layer granules into the punch, and press the granules of the two layers into contact with the double-layer chip using the tablet press. The final double-layer tablet core contains 309.4 mg of levodopa and 16.5 mg of carbidopa.

[0714] (4) Preparation of the osmotic pump tablet

[0715] Wrap the double-layer tablet core with a coating film. The raw material composition of the coating film contains 50 wt% cellulose acetate with an acetyl content of 39.8 wt%, 5 wt% polyethylene glycol 400, and 45 wt% copovidone VA 64 by weight percentage. Dissolve the raw material composition in acetone to make a 4% solution. Spray the solution onto the double-layer chip using a pan coater to form the coating film. Based on the obtained osmotic pump tablet, the coating film content is 7.0 wt%. Drill a 1.0-mm drug release hole in the coating film using a laser or mechanically.

[0716] (5) Preparation of the outer coating

[0717] The raw material composition of the outer coating includes 55.4 wt% of levodopa, 31.9 wt% of carbidopa, 10.0 wt% hydroxypropyl cellulose (EXF), 1.66 wt% dibutylhydroxytoluene, and 1.0 wt% triethyl citrate. Make these components into a 10 wt% solution in ethanol, and spray the solution onto the controlled-release tablet using a pan coater. The outer coating layer contains 18.75 mg of levodopa and 10.8 mg of carbidopa.

[0718] The double-layer osmotic pump tablet of this example can be held in the oral cavity. The release duration of about 85% of the active drug in the osmotic pump tablet is approximately 8 hours, and the released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0719] Preparation of the osmotic pump tablet in Example 56

[0720] An osmotic pump tablet designed, formed and adapted for use in conjunction with Example 30, the osmotic pump tablet containing the active drugs levodopa and carbidopa monohydrate, is prepared according to the following steps:

[0721] (1) Prepare the drug-containing layer, which consists of two parts. Based on the total weight of the drug-containing layer, the first part contains 54.9 wt% of levodopa, 15.0 wt% of hydroxypropyl cellulose with a weight-average molecular weight of 80,000, 8.07 wt% of mannitol and 0.9 wt% of aspartame. Each is sieved through a 40-mesh stainless steel sieve, then granulated by wet method and dried in a fluidized bed; sized through a 1.2-mm stainless steel sieve. The second part contains 3.16 wt% of carbidopa monohydrate, 11.8 wt% of mannitol and 5.0 wt% of poloxamer (P407). Each is sieved through a 40-mesh stainless steel sieve, then granulated by hot melt method and sized through a 1.2-mm stainless steel sieve. After mixing the first part and the second part of the granules, an additional 0.1 wt% of mint essence, 0.1 wt% of dibutylhydroxytoluene and 1.0 wt% of magnesium stearate are mixed to obtain the drug-containing layer granules.

[0722] (2) Prepare the push layer

[0723] Based on the total weight of the push layer, take 68.5 wt% of sodium carboxymethyl cellulose (7H4XF), 10.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF) and 0.5 wt% of iron oxide red; each is sieved through a 40-mesh stainless steel sieve, then granulated by dry method; sized through a 1.2-mm stainless steel sieve, and then mixed with 0.5 wt% of colloidal silica and 0.5 wt% of magnesium stearate to obtain the push layer granules.

[0724] (3) Prepare the double-layer tablet core

[0725] Press the drug-containing layer granules and the push layer granules into a double-layer chip, and the tablet pressing punch die is a 7.0-mm round punch. Add 563.9 mg of the drug layer granules into the tablet press punch and tamp them, then add 282.0 mg of the osmotic layer granules into the punch, and press the granules of the two layers with a tablet press to form a contact double-layer chip. The final double-layer tablet core contains 412.5 mg of levodopa and 23.8 mg of carbidopa.

[0726] (4) Prepare the osmotic pump tablet

[0727] Wrap the double-layer tablet core with a coating film. The raw material composition of the coating film contains 50 wt% of cellulose acetate with an acetyl content of 39.8 wt%, 5 wt% of polyethylene glycol 400, and 45 wt% of copovidone VA 64 by weight percentage. Dissolve this composition in acetone to make a 4% solution, and spray the solution onto the double-layer chip using a pan coater to form a coating film. Based on the resulting osmotic pump tablet, the coating film content is 5.5 wt%. Drill a 1.0 mm drug release hole in the coating film using a laser or mechanically.

[0728] The double-layer osmotic pump tablet in this example can be held in the oral cavity. The release duration of about 85% of the active drug in this osmotic pump tablet is approximately 8 hours, and the released drug in the oral cavity is continuously swallowed into the gastrointestinal tract, providing continuous and stable drug absorption and blood drug concentration. The retention amount of the drug active ingredient at the drug release site is less than 10%.

[0729] Example 57 Capsule-shaped tablet Specification 25 mg / 100 mg (carbidopa / levodopa)

[0730] The prescription is as shown in Table 5 below:

[0731] Table 5

[0732]

[0733] Preparation method:

[0734] (1) Prepare the drug-containing layer

[0735] Based on the total weight of the drug-containing layer, take 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32), and 18.0 wt% of mannitol, and then granulate by dry granulation; screen and size the granules through a 16-mesh stainless steel sieve, and then mix with 1.00 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0736] (2) Prepare the boosting layer

[0737] Based on the total weight of the boosting layer, take 55.0 wt% of sodium carboxymethylcellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose (EXF), and 0.50 wt% of iron oxide red, and then granulate by dry granulation; screen and size the granules through a 16-mesh stainless steel sieve, and then mix with 0.50 wt% of magnesium stearate to obtain the boosting layer granules.

[0738] (3) Prepare the double-layer tablet core

[0739] Press the drug-containing layer granules and the boosting layer granules into a double-layer tablet core, and the punch die size is (Shallow Concavity). Add the drug-containing layer granules (about 166.69 mg) obtained in step (1) into the punch of the tableting machine and tamp them. Then add the boosting layer granules (about 83.27 mg) obtained in step (2) into the punch, and press the granules of the two layers into a contact bilayer tablet core (about 249.96 mg) using the tableting machine.

[0740] (4) Prepare the osmotic pump tablet

[0741] Wrap the bilayer tablet core with a coating film. The raw material composition of the coating film includes 65.0 wt% of cellulose acetate and 35.0 wt% of copovidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. Dissolve this composition in acetone / absolute ethanol (V:V = 9:1), and the solid content is 4.0%. Spray this solution onto the bilayer tablet core using a pan coater to form a coating film, and the weight of the coating film accounts for about 10.0% of the weight of the bilayer tablet core. Then, a drug-containing immediate-release outer coating further wraps the coating film. The raw material composition of the drug-containing immediate-release outer coating includes 46.7 wt% of carbidopa monohydrate, 43.3 wt% of levodopa, and 10.0 wt% of hydroxypropyl cellulose (EXF) by weight percentage. Dissolve this composition in absolute ethanol, and the solid content is 10.0%. Spray this solution onto the coating film using a pan coater to form a drug-containing immediate-release outer coating, and obtain the osmotic pump tablet. Punch holes by mechanical punching or laser punching, and the aperture of the drug release hole is 1.0 mm. The specification of the osmotic pump tablet in this example is 25 mg / 100 mg (carbidopa / levodopa), and it is a round biconvex tablet.

[0742] Take this product, and according to the dissolution and release determination method (the first method in General Principles <0931> of the Chinese Pharmacopoeia and the first method of USP <711>), use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium, with a rotation speed of 75 revolutions per minute, and operate according to the law. Sampling is carried out at 0.5 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 8 hours.

[0743] The release time of the active pharmaceutical ingredient levodopa in this osmotic pump tablet lasts for about 6 hours (as Figure 39 shown), and the active ingredient carbidopa in the drug-containing immediate-release outer coating is released by 104% at 0.5 h, with an SD value of 10.5%.

[0744] Example 58 Capsule-shaped Tablet Specification 25 mg / 100 mg (carbidopa / levodopa)

[0745] The prescription is as follows in Table 6:

[0746] Table 6

[0747]

[0748] Preparation method:

[0749] (1) Preparation of the drug-containing layer

[0750] Taking 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32), 16.5 wt% of mannitol and 0.50 wt% of colloidal silicon dioxide based on the total weight of the drug-containing layer, and then performing dry granulation; screening and sizing through a 16-mesh stainless steel sieve, and then mixing with 2.00 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0751] (2) Preparation of the boosting layer

[0752] Taking 49.0 wt% of sodium carboxymethyl cellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF) and 0.5 wt% of iron oxide red based on the total weight of the boosting layer, and then performing dry granulation; screening and sizing through a 16-mesh stainless steel sieve, and then mixing with 0.5 wt% of magnesium stearate to obtain the boosting layer granules.

[0753] (3) Preparation of the double-layer tablet core

[0754] Pressing the drug-containing layer granules and the boosting layer granules into a double-layer tablet core, and the punch die size is (shallow concave). Adding the drug-containing layer granules (about 166.69 mg) obtained in step (1) into the punch of the tablet press and tamping, then adding the boosting layer granules (about 83.34 mg) obtained in step (2) into the punch, and pressing the granules of the two layers with the tablet press to form a contact double-layer tablet core (about 250.03 mg).

[0755] (4) Preparation of the osmotic pump tablet

[0756] The double-layer tablet core is wrapped with a coating film. The raw material composition of the coating film includes 65.0 wt% of cellulose acetate and 35.0 wt% of copovidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. The composition is dissolved in acetone / anhydrous ethanol (V:V = 9:1), and the solid content is 4.0%. The solution is sprayed onto the double-layer tablet core in a pan coater to form a coating film, and the weight of the coating film accounts for about 10.0% of the weight of the double-layer tablet core. Then, a drug-containing immediate-release outer coating further wraps the coating film. The raw material composition of the drug-containing immediate-release outer coating includes 46.7 wt% of carbidopa monohydrate, 43.3 wt% of levodopa, and 10.0 wt% of hydroxypropyl cellulose (EXF) by weight percentage. The composition is dissolved in anhydrous ethanol, and the solid content is 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, and an osmotic pump tablet is obtained. Punching is carried out by mechanical punching or laser punching, and the aperture of the drug release hole is 1.0 mm. In this example, the specification of the controlled-release tablet is 25 mg / 100 mg (carbidopa / levodopa), and it is a round biconvex tablet.

[0757] Take this product and operate according to the dissolution and release determination method (the first method in General Chapter <0931> of the Chinese Pharmacopoeia and the first method of USP <711>) with 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium and a rotation speed of 75 revolutions per minute. Samples are taken at 0.5 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 8 hours.

[0758] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 6 hours (as Figure 40 shown), and 104% of the active ingredient carbidopa in the drug-containing immediate-release outer coating is released at 0.5 h, with an SD value of 10.5%.

[0759] Example 59 Capsule-shaped tablet Specification 25 mg / 150 mg (carbidopa / levodopa)

[0760] The prescription is as follows in Table 7:

[0761] Table 7

[0762]

[0763] Preparation method:

[0764] (1) Prepare the drug-containing layer

[0765] Taking 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32) and 18.0 wt% of mannitol based on the total weight of the drug-containing layer, and then performing dry granulation; sizing through a 16-mesh stainless steel sieve, and then mixing with 1.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0766] (2) Preparation of the boosting layer

[0767] Taking 55.0 wt% of sodium carboxymethyl cellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose (EXF) and 0.50 wt% of iron oxide red based on the total weight of the boosting layer, and then performing dry granulation; sizing through a 16-mesh stainless steel sieve, and then mixing with 0.50 wt% of magnesium stearate to obtain boosting layer granules.

[0768] (3) Preparation of the double-layer tablet core

[0769] Press the drug-containing layer granules and the boosting layer granules into a double-layer tablet core, and the punch die size is (shallow concave). Add the drug-containing layer granules (about 250 mg) obtained in step (1) into the punch of the tablet press and tamp them, then add the boosting layer granules (about 125.06 mg) obtained in step (2) into the punch, and press the granules of the two layers with the tablet press to form a contact double-layer tablet core (about 375.06 mg).

[0770] (4) Preparation of the osmotic pump tablet

[0771] Wrap the double-layer tablet core with a coating film. The raw material composition of the coating film includes 65.0 wt% of cellulose acetate and 35.0 wt% of copolyvidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. Dissolve this composition in acetone / absolute ethanol (V:V = 9:1), and the solid content is 4.0%. Spray this solution onto the double-layer tablet core in a pan coater to form a coating film, and the weight of the coating film accounts for about 8.0% of the weight of the double-layer tablet core. Then, a drug-containing immediate-release outer coating further wraps the coating film. The raw material composition of the drug-containing immediate-release outer coating includes 37.7 wt% of carbidopa monohydrate, 52.3 wt% of levodopa and 10.0 wt% of hydroxypropyl cellulose (EXF) by weight percentage. Dissolve this composition in absolute ethanol, and the solid content is 10.0%. Spray this solution onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, and obtain the osmotic pump tablet. Punch holes by mechanical punching or laser punching, and the aperture of the drug release hole is 1.0 mm. The specification of the controlled-release tablet in this example is 25 mg / 150 mg (carbidopa / levodopa), and it is a round biconvex tablet.

[0772] Take this product and, according to the dissolution and release determination method (the first method in General Principles <0931> of Chinese Pharmacopoeia and the first method in USP <711>), use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium, with a rotation speed of 75 revolutions per minute, and operate according to the law. Sampling is carried out at 0.5 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 8 hours.

[0773] The release time of the active pharmaceutical ingredient levodopa in this osmotic pump tablet lasts for about 6 hours (as Figure 41 shown), and 96% of the active ingredient carbidopa in the drug-containing rapid-release outer coating is released at 0.5 h, with an SD value of 12%.

[0774] Example 60 Capsule-shaped tablets, specification 25 mg / 150 mg (carbidopa / levodopa)

[0775] The prescription is as shown in Table 8 below:

[0776] Table 8

[0777]

[0778] Preparation method:

[0779] (1) Prepare the drug-containing layer

[0780] Based on the total weight of the drug-containing layer, take 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32), 16.5 wt% of mannitol, and 0.50 wt% of colloidal silicon dioxide, and then granulate by dry granulation; screen and size the granules through a 16-mesh stainless steel sieve, and then mix with 2.00 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0781] (2) Prepare the boosting layer

[0782] Based on the total weight of the boosting layer, take 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF), and 0.50 wt% of iron oxide red, and then granulate by dry granulation; screen and size the granules through a 16-mesh stainless steel sieve, and then mix with 0.50 wt% of magnesium stearate to obtain the boosting layer granules.

[0783] (3) Prepare the double-layer tablet core

[0784] Press the drug-containing layer granules and the boosting layer granules into a double-layer tablet core, and the punch die size is (Shallow concave). Add the drug-containing layer granules (about 250.05 mg) obtained in step (1) to the punch of a tableting machine and tamp them down. Then, add the booster layer granules (about 125.06 mg) obtained in step (2) to the punch, and press the granules of the two layers into a contact bilayer tablet core (about 375.11 mg) using a tableting machine.

[0785] (4) Prepare an osmotic pump tablet

[0786] Wrap the bilayer tablet core with a coating film. The raw material composition of the coating film includes 65.0 wt% of cellulose acetate and 35.0 wt% of copovidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. Dissolve this composition in acetone / anhydrous ethanol (V:V = 9:1) with a solid content of 4.0%. Spray this solution onto the bilayer tablet core using a pan coater to form a coating film, and the weight of the coating film accounts for 8.0% of the weight of the bilayer tablet core. Then, a drug-containing rapid-release outer coating further wraps the coating film. The raw material composition of the drug-containing rapid-release outer coating includes 37.7 wt% of carbidopa monohydrate, 52.3 wt% of levodopa, and 10.0 wt% of hydroxypropyl cellulose (EXF) by weight percentage. Dissolve this composition in anhydrous ethanol with a solid content of 10.0%. Spray this solution onto the coating film using a pan coater to form a drug-containing rapid-release outer coating, and obtain an osmotic pump tablet. Punch holes by mechanical punching or laser punching, and the aperture of the drug release hole is 1.0 mm. In this example, the specification of the controlled-release tablet is 25 mg / 150 mg (carbidopa / levodopa), and it is a round biconvex tablet.

[0787] Take this product and, according to the dissolution and release determination method (the first method in General Principles <0931> of the Chinese Pharmacopoeia and the first method in USP <711>), use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium, with a rotation speed of 75 revolutions per minute, and operate according to the law. Sampling is carried out at 0.5 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 8 hours.

[0788] The release time of the active pharmaceutical ingredient levodopa in this osmotic pump tablet lasts for about 6 hours (as Figure 42 shown), and 96% of the active ingredient carbidopa in the drug-containing rapid-release outer coating is released at 0.5 h, with an SD value of 12%.

[0789] Example 61 Capsule-shaped tablet Specification 25 mg / 250 mg (carbidopa / levodopa)

[0790] The prescription is as follows in Table 9:

[0791] Table 9

[0792]

[0793] Preparation method:

[0794] (1) Preparation of the drug-containing layer

[0795] Based on the total weight of the drug-containing layer, take 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32), and 18.0 wt% of mannitol, and then perform dry granulation; screen the granules through a 16-mesh stainless steel sieve, and then mix with 1.00 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0796] (2) Preparation of the boosting layer

[0797] Based on the total weight of the boosting layer, take 55.0 wt% of sodium carboxymethyl cellulose, 34.0 wt% of sorbitol, 10.0 wt% of hydroxypropyl cellulose (EXF), and 0.50 wt% of iron oxide red, and then perform dry granulation; screen the granules through a 16-mesh stainless steel sieve, and then mix with 0.50 wt% of magnesium stearate to obtain the boosting layer granules.

[0798] (3) Preparation of the double-layer tablet core

[0799] Press the drug-containing layer granules and the boosting layer granules into a double-layer tablet core, and the punch die size is (shallow concave). Add the drug-containing layer granules (about 416.66 mg) obtained in step (1) into the punch of the tablet press and tamp them, then add the boosting layer granules (about 208.28 mg) obtained in step (2) into the punch, and press the granules of the two layers with the tablet press to form a contact double-layer tablet core (about 624.94 mg).

[0800] (4) Preparation of the osmotic pump tablet

[0801] The double-layer tablet core is wrapped with a coating film. The raw material composition of the coating film includes 65.0 wt% of cellulose acetate and 35.0 wt% of copovidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. The composition is dissolved in acetone / absolute ethanol (V:V = 9:1), and the solid content is 4.0%. The solution is sprayed onto the double-layer tablet core in a pan coater to form a coating film, and the weight of the coating film accounts for 6.5% of the weight of the double-layer tablet core. Then, a drug-containing immediate-release outer coating further wraps the coating film. The raw material composition of the drug-containing immediate-release outer coating includes 27.2 wt% of carbidopa monohydrate, 62.9 wt% of levodopa, and 10.0 wt% of hydroxypropyl cellulose (EXF) by weight percentage. The composition is dissolved in absolute ethanol, and the solid content is 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, and an osmotic pump tablet is obtained. Punching is carried out by mechanical punching or laser punching, and the aperture of the drug release hole is 1.0 mm. In this example, the specification of the controlled-release tablet is 25 mg / 250 mg (carbidopa / levodopa), and it is a round biconvex tablet.

[0802] Take this product and operate according to the dissolution and release determination method (the first method in General Principles <0931> of the Chinese Pharmacopoeia and the first method of USP <711>), using 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium, with a rotation speed of 75 revolutions per minute. Samples are taken at 0.5 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 8 hours.

[0803] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 6 hours (as Figure 43 shown), and 93% of the active ingredient carbidopa in the drug-containing immediate-release outer coating is released at 0.5 h, with an SD value of 4.6%.

[0804] Example 62 Capsule-shaped tablet Specification 25 mg / 250 mg (carbidopa / levodopa)

[0805] The prescription is as follows in Table 10:

[0806] Table 10

[0807]

[0808] Preparation method:

[0809] (1) Prepare the drug-containing layer

[0810] Taking 45.0 wt% of levodopa, 31.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32), 16.5 wt% of mannitol and 0.50 wt% of colloidal silicon dioxide based on the total weight of the drug-containing layer, then granulating by dry granulation; sizing through a 16-mesh stainless steel sieve, and then mixing with 2.00 wt% of magnesium stearate to obtain drug-containing layer granules.

[0811] (2) Preparation of the boosting layer

[0812] Taking 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF) and 0.5 wt% of iron oxide red based on the total weight of the boosting layer, then granulating by dry granulation; sizing through a 16-mesh stainless steel sieve, and then mixing with 0.5 wt% of magnesium stearate to obtain boosting layer granules.

[0813] (3) Preparation of the double-layer tablet core

[0814] Compress the drug-containing layer granules and the boosting layer granules into a double-layer tablet core, and the punch die size is (shallow concave). Add the drug-containing layer granules (about 416.71 mg) obtained in step (1) into the punch of the tablet press and tamp, then add the boosting layer granules (about 208.28 mg) obtained in step (2) into the punch, and compress the granules of the two layers with the tablet press to form a contacting double-layer tablet core (about 624.99 mg).

[0815] (4) Preparation of the osmotic pump tablet

[0816] Wrap the double-layer tablet core with a coating film. The raw material composition of the coating film includes 65.0 wt% of cellulose acetate and 35.0 wt% of copolyvidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. Dissolve this composition in acetone / absolute ethanol (V:V = 9:1), and the solid content is 4.0%. Spray this solution onto the double-layer tablet core in a pan coater to form a coating film, and the weight of the coating film accounts for about 6.5% of the weight of the double-layer tablet core. Then, a drug-containing rapid-release outer coating further wraps the coating film. The raw material composition of the drug-containing rapid-release outer coating includes 37.7 wt% of carbidopa monohydrate, 52.3 wt% of levodopa and 10.0 wt% of hydroxypropyl cellulose (EXF) by weight percentage. Dissolve this composition in absolute ethanol, and the solid content is 10.0%. Spray this solution onto the coating film in a pan coater to form a drug-containing rapid-release outer coating, and obtain the osmotic pump tablet. Punch holes by mechanical punching or laser punching, and the aperture of the drug release hole is 1.0 mm. The specification of the controlled-release tablet in this example is 25 mg / 250 mg (carbidopa / levodopa), and it is a round biconvex tablet.

[0817] Take this product and, according to the dissolution and release determination method (the first method in General Principles <0931> of Chinese Pharmacopoeia and the first method in USP <711>), use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium, with a rotation speed of 75 revolutions per minute, and operate according to law. Sampling is carried out at 0.5 hour, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, and 8 hours.

[0818] The release time of the active pharmaceutical ingredient levodopa in this osmotic pump tablet lasts for about 6 hours (as Figure 44 shown), and 93% of the active ingredient carbidopa in the drug-containing rapid-release outer coating is released at 0.5 h, with an SD value of 4.6%.

[0819] Example 63 Capsule-shaped tablets, specification 62.5 mg / 250 mg (carbidopa / levodopa)

[0820] The prescription is as follows in Table 11:

[0821] Table 11

[0822]

[0823] Preparation method:

[0824] (1) Prepare the drug-containing layer

[0825] Based on the total weight of the drug-containing layer, take 63.0 wt% of levodopa, 11.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32), 10.0 wt% of sorbitol, and 10.0 wt% of poloxamer (P407), and then granulate by dry granulation; screen and size the granules through a 16-mesh stainless steel sieve, and then mix with 1.00 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0826] (2) Prepare the boosting layer

[0827] Based on the total weight of the boosting layer, take 49.0 wt% of sodium carboxymethylcellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF), and 0.50 wt% of iron oxide red, and then granulate by dry granulation; screen and size the granules through a 16-mesh stainless steel sieve, and then mix with 0.50 wt% of magnesium stearate to obtain the boosting layer granules.

[0828] (3) Prepare the double-layer tablet core

[0829] Press the drug-containing layer granules and the boosting layer granules into a double-layer tablet core, and the punch die size is (Shallow Concavity). Add the drug-containing layer granules (about 396.76 mg) obtained in step (1) into the punch of the tablet press and tamp them. Then, add the booster layer granules (about 198.38 mg) obtained in step (2) into the punch, and press the granules of the two layers into a contact bilayer tablet core (about 595.14 mg) using the tablet press.

[0830] (4) Preparation of osmotic pump tablets

[0831] Wrap the bilayer tablet core with a coating film. The raw material composition of the coating film includes 65.0 wt% of cellulose acetate and 35.0 wt% of copovidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. Dissolve this composition in acetone / absolute ethanol (V:V = 9:1), and the solid content is 4.0%. Spray this solution onto the bilayer tablet core in a pan coater to form a coating film, and the weight of the coating film accounts for about 9.5% of the weight of the bilayer tablet core. Then, a drug-containing rapid-release outer coating further wraps the coating film. The raw material composition of the drug-containing rapid-release outer coating includes 90.0 wt% of carbidopa monohydrate and 10.0 wt% of hydroxypropyl cellulose (EXF) by weight percentage. Dissolve this composition in absolute ethanol, and the solid content is 10.0%. Spray this solution onto the coating film in a pan coater to form a drug-containing rapid-release outer coating, and obtain the osmotic pump tablet. Punch holes by mechanical punching or laser punching, and the aperture of the drug release hole is 1.0 mm. The specification of the controlled-release tablet in this example is 62.5 mg / 250 mg (carbidopa / levodopa), and it is a round biconvex tablet.

[0832] Take this product and operate according to the dissolution and release determination method (the first method in General Principles <0931> of the Chinese Pharmacopoeia and the first method of USP <711>) with 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium and a rotation speed of 75 revolutions per minute. Sampling is carried out at the 1st hour, 2nd hour, 3rd hour, 4th hour, 6th hour, 8th hour, and 10th hour.

[0833] The release time of the active pharmaceutical ingredient levodopa in this osmotic pump tablet lasts for about 10 hours (as Figure 45 shown), and 98% of the active ingredient carbidopa in the drug-containing rapid-release outer coating is released in 0.5 h, with an SD value of 6.4%.

[0834] Example 64 Capsule-shaped Tablets Specification 62.5 mg / 250 mg (carbidopa / levodopa)

[0835] The prescription is as follows in Table 12:

[0836] Table 12

[0837]

[0838] Preparation method:

[0839] (1) Preparation of the drug-containing layer

[0840] Based on the total weight of the drug-containing layer, take 63.0 wt% of levodopa, 11.0 wt% of hydroxypropyl cellulose (EXF), 5.00 wt% of polyvinylpyrrolidone (K29 / 32), 8.50 wt% of sorbitol, 10.0 wt% of poloxamer (P407), and 0.50 wt% of colloidal silica, and then granulate by dry granulation; screen and size the granules through a 16-mesh stainless steel sieve, and then mix with 2.00 wt% of magnesium stearate to obtain the drug-containing layer granules.

[0841] (2) Preparation of the booster layer

[0842] Based on the total weight of the booster layer, take 49.0 wt% of sodium carboxymethyl cellulose, 30.0 wt% of sorbitol, 20.0 wt% of hydroxypropyl cellulose (EXF), and 0.50 wt% of iron oxide red, and then granulate by dry granulation; screen and size the granules through a 16-mesh stainless steel sieve, and then mix with 0.50 wt% of magnesium stearate to obtain the booster layer granules.

[0843] (3) Preparation of the double-layer tablet core

[0844] Press the drug-containing layer granules and the booster layer granules into a double-layer tablet core, and the punch die size is (shallow concave). Add the drug-containing layer granules obtained in step (1) (about 396.72 mg) into the punch of the tablet press and tamp them, and then add the booster layer granules obtained in step (2) (about 198.38 mg) into the punch, and press the granules of the two layers with the tablet press to form a contact double-layer tablet core (about 595.1 mg).

[0845]

[0846] (4) Preparation of the osmotic pump tablet

[0847] ​The double-layer tablet core is wrapped with a coating film. The raw material composition of the coating film includes 65.0 wt% of cellulose acetate and 35.0 wt% of copovidone VA 64 by weight percentage, wherein the cellulose acetate is cellulose acetate containing 39.8 wt% of acetyl groups. The composition is dissolved in acetone / absolute ethanol (V:V = 9:1), and the solid content is 4.0%. The solution is sprayed onto the double-layer tablet core in a pan coater to form a coating film, and the weight of the coating film accounts for about 9.5% of the weight of the double-layer tablet core. Then, a drug-containing immediate-release outer coating further wraps the coating film. The raw material composition of the drug-containing immediate-release outer coating includes 90.0 wt% of carbidopa monohydrate and 10.0 wt% of hydroxypropyl cellulose (EXF) by weight percentage. The composition is dissolved in absolute ethanol, and the solid content is 10.0%. The solution is sprayed onto the coating film in a pan coater to form a drug-containing immediate-release outer coating, and an osmotic pump tablet is obtained. Punching is carried out by mechanical punching or laser punching, and the aperture of the drug release hole is 1.0 mm. In this example, the specification of the controlled-release tablet is 62.5 mg / 250 mg (carbidopa / levodopa), and it is a round biconvex tablet.

[0848] Take this product and, according to the dissolution and release determination method (the first method in General Principles <0931> of the Chinese Pharmacopoeia and the first method of USP <711>), use 900 mL of 0.1 mol / L hydrochloric acid solution as the dissolution medium, with a rotation speed of 75 revolutions per minute, and operate according to the law. Samples are taken at the 1st hour, 2nd hour, 3rd hour, 4th hour, 6th hour, 8th hour, and 10th hour.

[0849] The release time of the active pharmaceutical ingredient levodopa in the osmotic pump tablet lasts for about 10 hours (as Figure 46 shown), and 98% of the active ingredient carbidopa in the drug-containing immediate-release outer coating is released at 0.5 h, with an SD value of 6.4%.

[0850] Comparative Example A

[0851] Preparation of osmotic pump tablets (soaking experiment)

[0852] In this comparative example, the operation of Example 47 is repeated, with the difference that:

[0853] (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 polyvinylpyrrolidone (K29 / 32), 15.0 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint essence, and 1.0 wt% of magnesium stearate.

[0854] The release curve of the finally manufactured dosage form is measured in simulated saliva using the USPI paddle method. Figure 48The release curve of LD is described, and the release amount of the active drug fails to reach 85%. It is observed that the controlled-release membrane ruptures during the dissolution process, as Figure 47 shown.

[0855] Comparative Example B

[0856] Preparation of osmotic pump tablets (with a large amount of dissolution residue)

[0857] In this example, the operation of Example 47 was repeated, with the difference that: 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 polyvinylpyrrolidone (K29 / 32), 15.0 wt% of mannitol, 0.9 wt% of aspartame, 0.1 wt% of mint essence, and 1.0 wt% of magnesium stearate.

[0858] It is planned to measure the release curve of the finally manufactured dosage form in simulated saliva using the USPI paddle method. Figure 49 The release curve of LD is described, the release amount of the active drug fails to reach 85%, the residual amount of the active drug is large, and only 67.5% is released when the 4-hour release enters 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 has 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 has 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 has 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 excipients are binders.

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 5wt%-25wt%, for example 10wt%-20wt%, and for example 10wt%-15wt%; (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 methyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, and hydroxyethyl cellulose; (d) Based on the total weight of the drug-containing layer, the content of the surfactant is 1wt%-15wt%, for example 2wt%-10wt%, and again for example 5wt%-10wt%; (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 dodecyl benzene sulfonate, and sodium dodecyl sulfate; (g) Based on the total weight of the drug-containing layer, the content of the drug active ingredient is 50wt%-75wt%, for example 55wt%-65wt%, and again for example 58wt%-63wt%; (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 drugs are for example selected from one or more of nystatin, fluconazole, posaconazole, isavuconazole, voriconazole, anidulafungin, caspofungin, and micafungin; (k) The medicated 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 medicated 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 medicated 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 medicated 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 medicated 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 medicated 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 medicated 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 medicated 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%, such as 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%; such as 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%; such as 5 wt% - 10 wt%; Preferably, when the excipients contain lubricants, the lubricants are one or more of magnesium stearate, magnesium stearyl fumarate, talc powder, and colloidal silica; such as 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%; such as 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, 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 drug-containing layer, the content of the flavoring agents is 0 - 10 wt%, but not 0; such as 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 drug-containing layer, based on the total weight of the drug-containing layer, the content of the drug active ingredient is 30-75 wt%, for example 38 wt%-65 wt%. ⑤In the drug-containing layer, the drug active ingredient is (h) in Scheme (1). ⑥In the drug-containing layer, the drug active ingredient is selected from (i) in Scheme (1). ⑦In the drug-containing layer, the drug active ingredient is selected from (j) in Scheme (1). ⑧In the drug-containing layer, the excipients are selected from one or more of diluents, osmotic agents, acidulants, lubricants, flavoring agents, antioxidants, hydrophilic polymers, drug carriers, binders and surfactants. Preferably, when the excipients contain diluents, the diluents 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 diluents is preferably 0-50 wt% but not 0%; preferably 20-50 wt%, for example 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 acidulants, the acidulants 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 acidulants 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%, for example 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%; for example 2-5 wt%. Preferably, when the excipients contain hydrophilic polymers, the hydrophilic polymers are selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone and hydroxyethyl cellulose; preferably, based on the total weight of the drug-containing layer, the content of the hydrophilic polymers is 5 wt%-25 wt%, for example 10 wt%-20 wt%, for example 10 wt%-15 wt%. Preferably, when the adjuvant 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 adjuvant 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 adjuvant contains a surfactant, the surfactant is selected from one or more of poloxamer, polysorbate, glyceryl 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 of the following combinations: (a) A drug active ingredient, a hydrophilic polymer, a surfactant, a binder, a penetrant, a lubricant, and a flavoring agent; (b) A drug active ingredient, a hydrophilic polymer, a surfactant, a binder, a penetrant, a lubricant, an antioxidant, and a flavoring agent; (c) A drug active ingredient, a hydrophilic polymer, a surfactant, a penetrant, a lubricant, an antioxidant, and a flavoring agent; (d) A drug active ingredient, a hydrophilic polymer, a surfactant, a binder, a penetrant, and a lubricant; (i) A drug active ingredient, a filler, a penetrant, a hydrophilic polymer, an acidulant, and a lubricant; (ii) A drug active ingredient, a filler, a hydrophilic polymer, and a lubricant; (iii) A filler, a penetrant, a hydrophilic polymer, a lubricant, and a flavoring agent; (iv) A penetrant, a hydrophilic polymer, and a lubricant; (v) A filler, a hydrophilic polymer, a penetrant, and a lubricant; (vi) A filler, a penetrant, an acidulant, and a lubricant; (vii) A filler, a penetrant, a flavoring agent, and a lubricant; or (viii) A filler, an acidulant, and a lubricant; In Scheme (1), the drug-containing layer is any of the combinations of (a) to (d); In Scheme (2), the drug-containing layer is any of the combinations of (i) to (v); In Scheme (3), the drug-containing layer is any of the combinations of (a) to (d) and (i) to (viii).

4. The osmotic pump tablet according to claim 3, wherein The drug-containing layer is any 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 silica, 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 silica, 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% hypromellose, 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, wherein 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 satisfies 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, such as 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, wherein 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, and, for example, 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, wherein 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 sequentially laminated together 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 ethylcellulose, cellulose acetate, acrylic resin and microcrystalline cellulose, such as ethylcellulose; (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, ethylcellulose and acrylic resin, such as cellulose acetate, and further such as 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 further such as 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 quick-release outer coating; Preferably, the drug-containing quick-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 both; 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 rapid-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 rapid-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 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 excipients, 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 rapid-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, characterized in that, 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 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 tableting punch die used in the tableting method is preferably a 7.0 mm round punch; (5) The drug release holes are obtained by laser drilling or mechanical drilling.

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

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