Osmotic pump controlled release preparation, osmotic pump controlled release composition, preparation method and application

Abstract

The osmotic pump controlled release preparation comprises a tablet core containing a drug layer and a boosting layer, a controlled release coating layer with drug release holes and an optional water-soluble coating film which are sequentially arranged from inside to outside, wherein the drug release hole is communicated with the drug-containing layer and the exterior of the osmotic pump controlled release preparation; the boosting layer is positioned on one side, far away from the medicine release holes, of the medicine-containing layer; the drug-containing layer comprises active pharmaceutical ingredients, the boosting layer comprises a permeation promoting polymer, and the permeation promoting polymer comprises hydroxyethyl cellulose and alginate.

Description

Osmotic pump controlled-release preparation, osmotic pump controlled-release composition, preparation method and application

[0001] Related applications

[0002] This application claims priority to Chinese patent application number CN2022108875383, filed on July 26, 2022, entitled “Osmotic Pump Controlled Release Preparation, Osmotic Pump Controlled Release Composition, Preparation Method and Application,” the entire text of which is hereby incorporated by reference. Technical Field

[0003] The present application relates to the technical field of pharmaceutical preparations, and in particular to an osmotic pump controlled-release preparation, an osmotic pump controlled-release composition, a preparation method and applications. Background Art

[0004] Oral osmotic pump formulations were first developed by ALZA Corporation in the United States in 1970, and more than a dozen products have been launched since 1983. Currently, osmotic pump formulations are primarily used for drugs with short half-lives, frequent dosing requirements, and narrow therapeutic windows, such as those for chronic conditions such as cardiovascular disease, angina pectoris, hypertension, and asthma.

[0005] Traditional push-pull osmotic pumps with a double-layer core are semipermeable membrane-coated tablets with drug release apertures. The core consists of a drug-containing layer and a push layer. The drug-containing layer in the core is composed of the drug, a hydrophilic polymer carrier, and other excipients, while the push layer is composed of one or more sustained-release polymers, an osmotic pressure enhancer, and other excipients. The core is coated with a semipermeable membrane, and drug release apertures are formed on both sides of the semipermeable membrane. The drug is connected to the external environment through these apertures. One of the drug release mechanisms of double-layer push-pull osmotic pumps is the controlled swelling of the polymer in the push layer upon contact with water. This swelling pushes the drug-containing layer out of the membrane apertures, thereby achieving drug release. Therefore, the polymer in the push layer must have both swelling-boosting properties and appropriate swelling control to achieve controlled drug release. Therefore, the type and amount of polymer excipients in the push layer are key factors in controlling drug release in double-layer osmotic pump controlled-release tablets.

[0006] The polymers in the push layer of bilayer osmotic pump controlled-release tablets primarily utilize two types of functional excipients. One type is permeation-enhancing polymers that control the swelling rate of the push layer. These polymers are generally water-soluble and can gel after swelling with water. The high-viscosity gel can regulate the overall swelling rate of the push layer and control drug release. Known permeation-enhancing polymers include high-molecular-weight polyethylene oxide, carbomer, hydroxypropyl methylcellulose, povidone, copovidone, and hydroxypropyl cellulose. The other type of functional excipient in the push layer is insoluble polymers that rapidly swell in water. These insoluble polymers swell quickly in water and serve as the driving force for drug release from the push layer. Known water-insoluble polymers include sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone.

[0007] Osmotic-enhancing polymers are a class of polymers that inherently have strong water-absorbing and swelling properties. Some polymers can achieve multiple controlled-release functions with a single polymer component. For example, the push-pull osmotic pump products Adalat GITS (Baixintong) and Glucotrol XL (Ruyining), which are already available internationally, use high-viscosity polyethylene oxide as the primary osmotic-enhancing polymer excipient in the booster layer, achieving zero-order drug release. Flurbiprofen bilayer controlled-release tablets described in patent document CN103816131A and posaconazole bilayer controlled-release tablets described in patent document CN103948558A also use polyethylene oxide as the osmotic-enhancing polymer in the booster layer. However, the inventors of this application have discovered that polyethylene oxide has a low melting point and, when used as the primary excipient in tablet core compositions, is highly heat-sensitive. This can lead to "curling" during tablet compression due to heat generation. This protruding curling can easily create weak spots in the controlled-release coating, causing film rupture and drug burst release during release, increasing the risk of dose dumping.

[0008] Patent document CN101856337A describes an osmotic controlled-release drug delivery system using sodium alginate as a permeation-enhancing polymer. This polymer is used in combination with other polymers, such as copolyvidone and sodium carboxymethyl starch. This formulation requires a barrier coat between the inner surface of the controlled-release coating and the tablet core to reduce shear forces between the tablet core and the coating, thereby achieving relatively good drug release. Without the barrier coat, the drug release at 24 hours is only 83.4%.

[0009] The push-pull bilayer controlled-release tablets described in patent documents CN100563638C and CN100563637C use carbomer, hypromellose, copovidone, or a combination thereof as the primary penetration-enhancing polymer in the push layer. The nifedipine controlled-release formulation described in patent document CN100563637C uses carbomer as the penetration-enhancing polymer. However, due to the strong static charge of oral pharmaceutical-grade carbomer fine powder, it easily aggregates, resulting in poor uniformity during the powder mixing and granulation process, making tablet uniformity control difficult and even leading to unstable or incomplete release (release rate at 24 hours <90%) in some production batches. Other formulations that do not contain carbomer, such as those using hypromellose, copovidone, or a combination of the two as the penetration-enhancing polymer, suffer from insufficient driving force, leading to incomplete drug release (release rate at 24 hours <90%).

[0010] Based on this, it is necessary to further develop new osmotic pump controlled-release tablet preparations to achieve uniform and complete release of drugs.

[0011] Summary of the Invention

[0012] Based on this, it is necessary to provide an osmotic pump controlled-release preparation with a simple formulation that can control the stable release of the drug over 16 to 24 hours without the need for a barrier coating membrane, with a 24-hour release rate greater than 90%. Furthermore, an osmotic pump controlled-release composition for preparing the osmotic pump controlled-release preparation, as well as a preparation method and application thereof, are provided.

[0013] In a first aspect of the present application, an osmotic pump controlled-release preparation is provided, which comprises the following structures arranged in sequence from inside to outside:

[0014] A tablet core comprising a drug-containing layer and a booster layer;

[0015] a controlled-release coating layer with drug-releasing holes; and

[0016] An optional water-soluble coating film (the water-soluble coating film can serve as at least one of a moisture-proof coating film and an aesthetic coating).

[0017] Wherein, the drug-releasing hole communicates with the drug-containing layer and the outside of the osmotic pump controlled-release preparation; the booster layer is located on the side of the drug-containing layer away from the drug-releasing hole;

[0018] Wherein, the drug-containing layer is composed of a pharmaceutical active ingredient, a hydrophilic polymer carrier and a pharmaceutical excipient F1; wherein, the pharmaceutical excipient F1 is a pharmaceutical excipient different from the hydrophilic polymer carrier;

[0019] The boost layer is composed of a penetration-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure enhancer and a pharmaceutical excipient F2; wherein the penetration-promoting polymer contains hydroxyethyl cellulose and alginate; the water-insoluble swelling polymer includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone; wherein the pharmaceutical excipient F2 is a pharmaceutical excipient different from the penetration-promoting polymer, the water-insoluble swelling polymer and the osmotic pressure enhancer.

[0020] In some embodiments, the penetration-promoting polymer comprises hydroxyethyl cellulose and sodium alginate, and the water-insoluble swelling polymer is any one of carboxymethyl starch salt, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, or a combination thereof; or

[0021] The penetration-promoting polymer is hydroxyethyl cellulose and sodium alginate, and the water-insoluble swelling polymer includes at least one of carboxymethyl starch salt, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone; or,

[0022] The penetration-promoting polymer is hydroxyethyl cellulose and sodium alginate, and the water-insoluble swelling polymer is any one of carboxymethyl starch salt, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, or a combination thereof.

[0023] In some embodiments, the osmotic pump controlled-release formulation satisfies one or more of the following characteristics:

[0024] Based on the total weight of the drug-containing layer, the active pharmaceutical ingredient accounts for 4% to 33% of the weight of the drug-containing layer, the hydrophilic polymer carrier accounts for 40% to 96% (optionally 40% to 95%, alternatively 40% to 94%, alternatively 65% ​​to 96%, alternatively 65% ​​to 94%, alternatively 65% ​​to 85%) of the weight of the drug-containing layer, and the pharmaceutical excipient F1 accounts for 0 to 2% of the weight of the drug-containing layer;

[0025] Based on the total weight of the push layer, the penetration-promoting polymer accounts for 11% to 66% of the weight of the push layer (optionally 12% to 65%, alternatively 20% to 65%, alternatively 11% to 50%, alternatively 20% to 50%, and alternatively 20% to 40%), the water-insoluble swellable polymer accounts for 12% to 71% of the weight of the push layer (optionally 13% to 70%, further optionally 15% to 60%, further optionally 20% to 50%, and further optionally 20% to 40%), the osmotic pressure enhancer accounts for 10% to 45% of the weight of the push layer (optionally 14% to 42%, further optionally 15% to 40%), and the pharmaceutical excipient F2 accounts for 0.5% to 2.5% of the weight of the push layer;

[0026] The weight ratio of the drug-containing layer to the booster layer is 0.5-2, optionally 0.8-1.6, further optionally 0.8-1.5, further optionally 0.9-1.5;

[0027] The controlled-release coating layer with drug-releasing holes has a weight gain of 6% to 25% of the weight of the tablet core, optionally 6% to 21%, further optionally 8% to 25%, further optionally 8% to 15%, further optionally 10% to 20%.

[0028] In some embodiments, based on the total weight of the drug-containing layer, the active pharmaceutical ingredient accounts for 4% to 33% of the weight of the drug-containing layer, the hydrophilic polymer carrier accounts for 40% to 96% (optionally 40% to 95%, alternatively 40% to 94%, alternatively 65% ​​to 96%, alternatively 65% ​​to 94%, alternatively 65% ​​to 85%) of the weight of the drug-containing layer, and the pharmaceutical excipient F1 accounts for 0 to 2% of the weight of the drug-containing layer;

[0029] Based on the total weight of the push layer, the penetration-promoting polymer accounts for 11% to 66% of the weight of the push layer (optionally 12% to 65%, alternatively 20% to 65%, alternatively 11% to 50%, alternatively 20% to 50%, and alternatively 20% to 40%), the water-insoluble swellable polymer accounts for 12% to 71% of the weight of the push layer (optionally 13% to 70%, further optionally 15% to 60%, further optionally 20% to 50%, and further optionally 20% to 40%), the osmotic pressure enhancer accounts for 10% to 45% of the weight of the push layer (optionally 14% to 42%, further optionally 15% to 40%), and the pharmaceutical excipient F2 accounts for 0.5% to 2.5% of the weight of the push layer;

[0030] The weight ratio of the drug-containing layer to the booster layer is 0.5-2, optionally 0.8-1.6, further optionally 0.8-1.5, further optionally 0.9-1.5;

[0031] The weight gain of the controlled-release coating layer with drug-releasing holes is 6% to 25% of the weight of the tablet core, optionally 6% to 21%, further optionally 8% to 25%, further optionally 8% to 15%, further optionally 10% to 20%.

[0032] In some embodiments, no separator film is included between the core tablet and the controlled release coating layer.

[0033] In some embodiments, the osmotic pump controlled-release formulation satisfies one or more of the following characteristics:

[0034] The boost layer does not contain polyethylene oxide;

[0035] The boost layer does not contain carbomer;

[0036] The alginate in the penetration-promoting polymer is selected from one or more of sodium alginate, potassium alginate and ammonium alginate.

[0037] In some embodiments, the osmotic pump controlled-release formulation satisfies one or more of the following characteristics:

[0038] There are one or more drug release holes, and any one of the drug release holes communicates with the drug-containing layer and the outside of the osmotic pump controlled-release preparation;

[0039] The diameter of the drug-releasing hole is 0.6-1.0 mm.

[0040] In some embodiments, the drug-containing layer satisfies one or more of the following characteristics:

[0041] The hydrophilic polymer carrier is povidone, copovidone or a combination thereof;

[0042] The pharmaceutical excipient F1 is selected from one or more of an anti-osmotic agent, an antistatic agent and a lubricant.

[0043] In some embodiments, the drug-containing layer satisfies one or more of the following characteristics:

[0044] The penetration enhancer is selected from one or more of sodium chloride, potassium chloride, sorbitol, xylitol, glucose and sucrose, and may be sodium chloride;

[0045] The antistatic agent includes one or more of micro-powder silica gel, stearic acid and polyethylene glycol, and micro-powder silica gel can be selected;

[0046] The lubricant is selected from one or more of magnesium stearate, polyethylene glycol, sodium stearyl fumarate and talc.

[0047] In some embodiments, in the push-assist layer, the penetration-enhancing polymer mainly comprises hydroxyethyl cellulose and alginate;

[0048] Optionally, the sum of the weights of the hydroxyethyl cellulose and the alginate accounts for more than 80% by weight of the penetration-enhancing polymer.

[0049] In some embodiments, the boost layer satisfies one or more of the following characteristics:

[0050] The weight ratio of the hydroxyethyl cellulose to the alginate is 1:(1-60), optionally 1:(1.5-40), further optionally 1:(1.5-25), further optionally 1:(1.5-20), further optionally 1:(1.5-16);

[0051] The weight proportion of the hydroxyethyl cellulose in the boosting layer is 0.4% to 22% (optionally 0.5% to 20%).

[0052] In some embodiments, in the push layer, the pharmaceutical excipient F2 is selected from one or more of a lubricant, a colorant, and a glidant.

[0053] In some embodiments, in the push layer, the water-insoluble swellable polymer includes at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, and optionally includes one or more of cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone.

[0054] In some embodiments, in the boost layer, the osmotic pressure enhancer is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, sorbitol, xylitol, glucose and sucrose, and sodium chloride may be selected.

[0055] In some embodiments, the controlled-release coating layer with drug-releasing pores is composed of a semipermeable controlled-release coating membrane material and an optional pharmaceutical excipient F3; wherein the pharmaceutical excipient F3 is one or more of a plasticizer and a pore-forming agent.

[0056] In some embodiments, the osmotic pump controlled-release formulation satisfies one or more of the following characteristics:

[0057] The semipermeable controlled-release coating material is cellulose acetate or a premixed coating powder containing cellulose acetate;

[0058] The pharmaceutical excipient F3 is selected from one or more of polyethylene glycol, diethyl phthalate, triethyl citrate, triacetin and dibutyl sebacate;

[0059] The weight ratio of the pharmaceutical excipient F3 to the sum of the weight of the semipermeable controlled-release coating material and the pharmaceutical excipient F3 is 0-20%, optionally 1%-10%, and further optionally 1%-7.4%.

[0060] In some embodiments, the weight gain of the water-soluble coating film is 8% to 20% of the sum of the weights of the tablet core and the controlled-release coating layer with drug-releasing holes.

[0061] In some embodiments, the pharmaceutically active ingredient is selected from any one of nifedipine, glipizide, oxybutynin hydrochloride, doxazosin mesylate, and paliperidone.

[0062] In some embodiments, the pharmaceutically active ingredient is nifedipine.

[0063] In some embodiments, the drug-containing layer and the push layer constitute a bilayer core.

[0064] In some embodiments, the osmotic pump controlled-release formulation is controlled-released at 37° C. and 100 rpm, and the release behavior of the active pharmaceutical ingredient in the osmotic pump controlled-release formulation satisfies one or more of the following release properties:

[0065] The release rate at 4 hours was greater than 4%;

[0066] The release at 12 hours is greater than 40%; and

[0067] The release rate at 24 hours is greater than 90%;

[0068] Optionally, the release medium is 900 mL of 1% sodium lauryl sulfate in phosphate-citrate buffer, 900 mL of artificial intestinal fluid without pancreatic enzymes, 500 mL of 0.1 mol / L hydrochloric acid solution, 900 mL of 0.1 mol / L hydrochloric acid solution, or 500 mL of 0.2% (w / v) sodium chloride in 0.1 mol / L hydrochloric acid solution.

[0069] In the second aspect of the present application, an osmotic pump controlled-release composition is provided, which is composed of the components of the osmotic pump controlled-release preparation according to the first aspect of the present application and is used to prepare the osmotic pump controlled-release preparation.

[0070] In a third aspect of the present application, a method for preparing an osmotic pump controlled-release preparation is provided, which can be used to prepare the osmotic pump controlled-release preparation described in the first aspect of the present application, and the preparation method comprises the following steps in sequence:

[0071] Prepare drug-containing layer granules according to the components of the drug-containing layer, and prepare booster layer granules according to the components of the booster layer;

[0072] Pressing the drug-containing layer particles and the push-layer particles into the tablet core in a mold;

[0073] Coating the outer surface of the tablet core with a controlled-release coating layer, and then punching holes in the controlled-release coating layer to form the controlled-release coating layer with drug-releasing holes;

[0074] Optionally, the water-soluble coating film is coated.

[0075] In the fourth aspect of the present application, a boost layer composition is provided, which is composed of a permeation-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure enhancer and a pharmaceutical excipient F2; wherein,

[0076] The definitions of the penetration-promoting polymer, the water-insoluble swelling polymer, the osmotic pressure enhancer and the pharmaceutical excipient F2 are as defined in the first aspect of the present application;

[0077] Optionally, the penetration-promoting polymer is a combination of hydroxyethyl cellulose and alginate.

[0078] In a fifth aspect of the present application, there is provided a use of the osmotic pump controlled-release preparation according to the first aspect of the present application as an oral controlled-release preparation.

[0079] In a sixth aspect of the present application, there is provided a use of the osmotic pump controlled-release preparation of the first aspect of the present application, or the osmotic pump controlled-release composition of the second aspect of the present application, or the booster layer composition of the fourth aspect of the present application in the preparation of a drug for preventing and / or treating cardiovascular diseases, wherein the active ingredient of the drug is nifedipine, and the cardiovascular diseases include at least one of hypertension and chronic stable angina pectoris of coronary heart disease;

[0080] Herein, "prevention and / or treatment of cardiovascular diseases" refers to at least one aspect of prevention of cardiovascular diseases and treatment of cardiovascular diseases.

[0081] In a seventh aspect of the present application, a method for preventing cardiovascular disease is provided, comprising administering to a subject a preventively effective amount of the osmotic pump controlled-release preparation of the first aspect of the present application, or administering to a subject a preventively effective amount of the osmotic pump controlled-release composition of the second aspect of the present application;

[0082] Optionally, the cardiovascular disease includes at least one of hypertension and chronic stable angina pectoris of coronary heart disease.

[0083] In an eighth aspect of the present application, a method for treating cardiovascular disease is provided, comprising administering to a subject a therapeutically effective amount of the osmotic pump controlled-release preparation described in the first aspect of the present application, or administering to a subject a therapeutically effective amount of the osmotic pump controlled-release composition described in the second aspect of the present application;

[0084] Optionally, the cardiovascular disease includes at least one of hypertension and chronic stable angina pectoris of coronary heart disease.

[0085] In a ninth aspect of the present application, an osmotic pump controlled-release preparation for at least one of preventing and treating cardiovascular diseases is provided, wherein the osmotic pump controlled-release preparation is as defined in the first aspect of the present application.

[0086] In a tenth aspect of the present application, an osmotic pump controlled-release composition for at least one of preventing and treating cardiovascular diseases is provided, wherein the osmotic pump controlled-release composition is as defined in the first aspect of the present application.

[0087] After extensive research and exploration, the inventors of the present application unexpectedly discovered in the process of studying the expansion mechanism of the booster layer that alginate (such as sodium alginate) and hydroxyethyl cellulose are used as the main permeation-promoting polymeric excipients, and are combined with insoluble swelling polymers (one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, etc.) and osmotic pressure enhancers to construct a booster layer composition, which is then combined with the drug-containing layer to form a tablet core. The components cooperate with each other and act synergistically. The osmotic pump controlled-release preparation prepared in this way can achieve complete release within 16 to 24 hours (final release amount >90%), and can achieve complete drug release for 24 hours (release rate >90%) without the need for an isolation coating membrane; in addition, when the booster layer is prepared using the above composition, there is no or basically no agglomeration phenomenon during the preparation, mixing or tableting process, the tablet mixing uniformity is good, and the production process quality controllability is good. The inventors speculate that the mechanism is as follows: based on the interaction between the alginate molecular chains and the hydroxyethyl cellulose molecular chains, the combination of hydroxyethyl cellulose and alginate can form a new three-dimensional network hydrogel system with both high strength and high toughness, thereby improving the mechanical properties of the booster layer composition (including good compressibility and tensile properties). The high-strength hydrogel formed can synergistically promote the uniform release of the active ingredients in the drug-containing layer of this product, increase the final release amount of the drug, and help to achieve complete release of the drug.

[0088] In addition, during the preparation and implementation of this application, it was found that the addition of the permeation-promoting polymer hydroxyethyl cellulose can also improve the adhesion between the particles of each component in the booster layer, improve the compression force of the double-layer tablet core, help reduce the damage to the tablet surface during the coating process, and thus improve the release stability of the osmotic pump controlled-release preparation.

[0089] The push layer composition provided in this application is composed of a specific permeation-promoting polymer (optionally a combination of alginate and hydroxyethyl cellulose, wherein the alginate is such as sodium alginate) and a suitable water-insoluble swelling polymer (such as at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, further such as at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, further such as sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or a combination of the two), an osmotic pressure enhancer and other push layer excipients (pharmaceutical excipient F2). The high-strength and high-toughness hydrogel formed helps to improve the mechanical properties of the push layer composition hydrogel, promotes the release of drugs and excipients in the drug-containing layer through the drug release pores of the controlled release coating layer at a controlled release rate, and can ensure the uniform release of the active ingredient in the drug-containing layer, thereby increasing the final release amount of the drug (24-hour point release >90%) and facilitating complete drug release. The booster layer composition can be applied to the preparation and controlled-release administration of a variety of active ingredients, including but not limited to glipizide, oxybutynin hydrochloride, doxazosin mesylate and paliperidone, and can achieve stable controlled release in different dissolution media and complete drug release.

[0090] Compared with traditional osmotic pump controlled-release tablets, the osmotic pump controlled-release preparation provided in this application uses the aforementioned unexpectedly discovered booster layer composition, and also has the following beneficial effects: the excipients have good stability and are not easy to aggregate during the preparation process, the release of the active ingredients in the product is more stable, and the release rate difference between tablets is small. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more completely understand the present application and its beneficial effects, a brief introduction to the drawings required for the description of the embodiments will be given below. Obviously, the drawings described below are only some embodiments of the present application. For those skilled in the art, other drawings can be obtained based on these drawings without creative work. It should also be noted that the drawings are all drawn in a simplified form and are only used to conveniently and clearly assist in explaining the present application. The various dimensions of each component shown in the drawings are arbitrarily shown and may be accurate or not drawn to scale. For example, in order to make the illustrations clearer, the dimensions of the components are appropriately exaggerated in some places in the drawings. Unless otherwise specified, the components in the figures are not drawn to scale. This application does not limit every dimension of every component.

[0092] In the following description, the same reference numerals denote the same parts.

[0093] FIG1 is a schematic diagram of the structure of an osmotic pump controlled-release preparation in one embodiment of the present application, wherein A and B correspond to schematic diagrams of different numbers of drug release holes;

[0094] FIG2 is a schematic diagram of the structure of an osmotic pump controlled-release preparation in one embodiment of the present application;

[0095] FIG3 is a graph showing the average cumulative release curves of nifedipine controlled-release tablets of Prescriptions 1 to 10 in 900 mL of medium in the preparation examples;

[0096] FIG4 is a graph showing the average cumulative release curves of nifedipine controlled-release tablets in 900 mL of medium for comparative prescriptions 1 to 8 in the preparation examples;

[0097] Figure 5 is a microscopic observation of the push layer section of the nifedipine controlled-release tablets of Prescription 1 and Comparative Prescription 2 in the Preparation Example; wherein A is a cross-sectional view of the push layer of Tablet 1 of Comparative Prescription 2; B is a cross-sectional view of the push layer of Tablet 2 of Comparative Prescription 2; C is a cross-sectional view of the push layer of Tablet 1 of Prescription 1; and D is a cross-sectional view of the push layer of Tablet 2 of Prescription 1.

[0098] FIG6 is a release curve diagram of glipizide controlled-release tablets of Prescription 11 in the preparation example;

[0099] FIG7 is a release curve diagram of Oxybutynin Hydrochloride Controlled Release Tablets, Prescription 12, in the Preparation Example;

[0100] FIG8 is a release curve diagram of doxazosin mesylate controlled-release tablets in the preparation of prescription 13 in the example;

[0101] FIG9 is a release curve of paliperidone controlled-release tablets in the preparation of prescription 14 in the example;

[0102] FIG10 is a graph showing the release curves of nifedipine controlled-release tablets in 100 mL of medium from Preparation Example Prescription 1 and Comparative Prescription 2;

[0103] FIG11 is a graph showing the release curves of nifedipine controlled-release tablets in 5%, 10%, 20%, and 40% ethanol release media according to Prescription 2 in the Preparation Example;

[0104] FIG12 is a graph showing the release curves of nifedipine controlled-release tablets in 5%, 10%, 20%, and 40% ethanol release media in the preparation of comparative prescription 2 in the example;

[0105] FIG13 is a graph showing the release curves of nifedipine controlled-release tablets of Prescription 2 and Comparative Prescription 3 in artificial intestinal fluid in the preparation examples;

[0106] FIG14 is a graph showing the blood drug concentration-time curves of nifedipine controlled-release tablets of Prescription 6 and Comparative Prescription 3 in the Preparation Example after oral administration to dogs;

[0107] Figure 15 shows the friability test results of controlled-release tablets with different formulations in the coating pan.

[0108] Description of reference numerals:

[0109] In Figure 1: 1 is the drug-containing layer; 2 is the booster layer; 3 is the controlled release coating layer (controlled release coating membrane); 4 is the drug release hole;

[0110] In Figure 2: 1 is the drug-containing layer; 2 is the booster layer; 3 is the controlled-release coating layer (controlled-release coating membrane); 4 is the drug-releasing hole; 5 is the water-soluble coating membrane. DETAILED DESCRIPTION

[0111] Below in conjunction with accompanying drawing, embodiment and example, the application is described in further detail.It should be understood that these embodiment and example are only used to illustrate the application and are not used to limit the scope of the application, and the purpose of providing these embodiment and example is to make the understanding of the disclosure of the application more thorough and comprehensive.It should also be understood that the application can be implemented in many different forms and is not limited to the embodiment and example described herein. Those skilled in the art can make various changes or modifications without violating the connotation of the application, and the equivalent form obtained also falls within the protection scope of the application.In addition, in the description below, a large amount of details are given in order to provide a more complete understanding of the application, and it should be understood that the application can be implemented without one or more of these details.

[0112] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing embodiments and examples only and are not intended to limit this application.

[0113] the term

[0114] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0115] The terms "and / or", "or / and", and "and / or" used herein include any one of two or more related listed items, and also include any and all combinations of the related listed items, wherein the arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions: A, B, and "A+B (that is, a combination of A and B)". For another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (i.e., a technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, a combination of any two or any three of A, B, C, and D, and also includes a combination of four of A, B, C, and D (i.e., a technical solution that is all connected by "logical AND"). For another example, the technical solution of "having the following characteristics: A, and / or, B, and / or, C, and / or, D" can be understood as "satisfying one or more of the following characteristics: A, B, C, and D."

[0116] In this application, "multiple", "multiple", "multiple times", "multiple items", etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, "one or more" means one or more than or equal to two, and "one or more items" means one or more than or equal to two.

[0117] In the present invention, unless otherwise specified, "one or more" refers to any one of the listed items or any combination of the listed items. Similarly, "one or more," "one or more," and other expressions that mean "one or more" are to be understood in the same manner unless otherwise specified.

[0118] As used herein, "combination thereof", "any combination thereof", "any combination thereof" and the like include all suitable combinations of any two or more of the listed items.

[0119] Herein, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc. shall be based on the ability to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0120] Herein, "optional", "better", "more preferred", and "suitable" are merely descriptions of implementation methods or examples with better effects, and it should be understood that they do not constitute a limitation on the scope of protection of this application. If multiple "optional" items appear in a technical solution, unless otherwise specified and there are no contradictions or mutual constraints, each "optional" item is independent of the other. In a technical solution, when "optional" and one or more "alternative optional" items appear at the same time, any two or any more "optional" items may not be combined, or they may be combined to form different features.

[0121] In this application, the terms "further," "further," "particularly," "for example," "such as," "example," and "for example" are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this application. In the present invention, unless otherwise specified, "A (such as B)" means that B is a non-limiting example of A, and it should be understood that A is not limited to B.

[0122] In this application, "optionally", "optional", and "optional" mean optional, that is, any one of the two parallel options of "with" or "without". If multiple "optional" items appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" item is independent of each other. For example, descriptions such as "optionally contain" and "optionally include" in this application mean "containing or not containing". "Optional component X" means that component X is present or not. For example, "optionally is" means that it can be "or not be".

[0123] In this application, the terms "first," "second," "third," "fourth," etc. in "the first aspect," "the second aspect," "the third aspect," "the fourth aspect," etc. are used for descriptive purposes only and should not be understood as indicating or implying relative importance or quantity, nor should they be understood as implicitly indicating the importance or quantity of the indicated technical features. Furthermore, "first," "second," "third," "fourth," etc. serve only as non-exhaustive enumeration and description, and should be understood not to constitute a closed-ended limitation on quantity.

[0124] As used herein, the terms "comprising," "including," and "comprising" are synonymous and are inclusive or open-ended and do not exclude additional, unrecited elements.

[0125] In this application, the technical features or technical solutions described in open language include closed technical features or technical solutions composed of the listed contents, and also include open technical features or technical solutions containing the listed contents.

[0126] In this application, when it comes to a numerical interval (i.e., a numerical range), unless otherwise specified, the distribution of the optional numerical values ​​in the numerical interval is considered continuous and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical interval, and each numerical value between the two numerical endpoints. Unless otherwise specified, when a numerical interval only refers to an integer in the numerical interval, including the two endpoint integers of the numerical range and each integer between the two endpoints is equivalent to directly enumerating each integer. When multiple numerical ranges are provided to describe a feature or characteristic, these numerical ranges can be merged. In other words, unless otherwise specified, the numerical range disclosed herein should be understood to include any and all subranges included therein. The "numerical value" in the numerical interval can be any quantitative value, such as a number, a percentage, a ratio, etc. "Numerical interval" allows for broadly including quantitative intervals such as percentage intervals, ratio intervals, and ratio intervals.

[0127] Unless otherwise specified, the temperature parameters in this application allow for both constant temperature treatment and temperature fluctuations within a certain temperature range. It should be understood that the constant temperature treatment allows for temperature fluctuations within the accuracy range of instrument control. Fluctuations within ranges such as ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are permitted.

[0128] In this application, the term "room temperature" generally refers to 4°C to 35°C, preferably 20°C ± 5°C. In some embodiments of this application, room temperature refers to 20°C to 30°C.

[0129] In this application, when referring to a data range, if the unit is only after the right endpoint, it means that the units of the left and right endpoints are the same. For example, 3~5h means that the units of the left endpoint "3" and the right endpoint "5" are both h (hours).

[0130] In this application, unless otherwise specified, "about" means within a certain range above or below the number, and the fluctuation range may vary depending on the type and value of the number. This fluctuation range can be reasonably determined based on the accuracy of the test or measurement method. For example, "about 10 mg" can mean 10 ± 0.4 mg, etc.

[0131] In this application, the "molecular weight" of a polymer refers to the weight average molecular weight unless otherwise specified.

[0132] All documents mentioned in this application are cited as references in this application, just as each document is cited as a reference individually. Unless they conflict with the invention purpose and / or technical solution of this application, the cited documents involved in this application are cited in their entirety and for all purposes. When cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When cited documents are involved in this application, the examples and optional methods of the cited relevant technical features may also be incorporated into this application as references, but are limited to the ability to implement this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be adaptively amended according to the description in this application.

[0133] In the present invention, if a method flow involves multiple steps, unless otherwise expressly stated herein, there is no strict order restriction on the execution of these steps, and they may be executed in an order other than that described. Moreover, any step may include multiple sub-steps or multiple stages, and these sub-steps or stages do not necessarily need to be completed at the same time, but may be executed at different times, and their execution order does not necessarily need to be sequential, but may be executed in rotation, alternation, or simultaneously with other steps or parts of sub-steps or stages of other steps.

[0134] In this application, the term "pharmaceutical excipient" should be understood to refer to pharmaceutically acceptable excipients that comply with current pharmaceutical excipient management standards.

[0135] In this application, "pharmaceutically acceptable" means suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit / risk ratio.

[0136] In this application, "patient" refers to an animal, which may be a mammal, preferably a human. The term "mammal" primarily refers to warm-blooded vertebrate mammals, including but not limited to cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs, cows, sheep, horses, and humans.

[0137] In the present application, "pharmaceutical excipient F1" is a pharmaceutical excipient in the drug-containing layer that is different from the hydrophilic polymer carrier; "pharmaceutical excipient F2" is a pharmaceutical excipient in the push-boost layer that is the same as the hydrophilic polymer carrier; "pharmaceutical excipient F3" is a pharmaceutical excipient in the controlled-release coating layer with drug-releasing pores, which can be a plasticizer and / or a pore-forming agent (i.e., one or more plasticizers and pore-forming agents).

[0138] In this application, unless otherwise specified, "release at time point XX" refers to the percentage of the cumulative release from the start of release (0 hours) to time point XX as a percentage of the theoretical total release. For example, "release at time point 4 hours" refers to the cumulative release from 0 to 4 hours, which can be expressed as a percentage.

[0139] In the first aspect of the present application, an osmotic pump controlled-release formulation is provided, comprising the following structure, arranged from inside to outside: a tablet core comprising a drug-containing layer and a push layer, a controlled-release coating layer with a drug-release aperture, and an optional water-soluble coating membrane; wherein the drug-release aperture connects the drug-containing layer to the exterior of the osmotic pump controlled-release formulation; the push layer is located on the side of the drug-containing layer away from the drug-release aperture; the drug-containing layer contains the active pharmaceutical ingredient, and the push layer includes a permeation-enhancing polymer comprising hydroxyethyl cellulose and alginate. The formulation is simple, and the duration and release rate of stable drug release can be precisely controlled without the need for a barrier coating membrane. For example, stable drug release can be controlled over 16 to 24 hours, with a 24-hour release rate greater than 90%.

[0140] In some embodiments, the osmotic pump controlled-release preparation comprises a double-layer core structure, and further, the double-layer core structure comprises a drug-containing layer and a push-boost layer.

[0141] In some embodiments, the tablet core comprising the drug-containing layer and the push-boost layer is a double-layer tablet core structure.

[0142] In some embodiments, the core tablet comprising a drug-containing layer and a push layer is composed of the drug-containing layer and the push layer.

[0143] In some embodiments, the drug-releasing hole is located on only one side of the drug-containing layer, that is, on a single side.

[0144] In some embodiments, an osmotic pump controlled-release formulation is provided, comprising the following structure, arranged from inside to outside: a bilayer tablet core comprising a drug-containing layer and a push layer, a controlled-release coating layer with a drug-release aperture, and an optional water-soluble coating. The drug-release aperture connects the drug-containing layer to the exterior of the osmotic pump controlled-release formulation, and the drug-release aperture is located on one side of the drug-containing layer; the push layer is located on the side of the drug-containing layer away from the drug-release aperture. The drug-containing layer contains the active pharmaceutical ingredient, and the push layer includes a permeation-enhancing polymer comprising hydroxyethyl cellulose and alginate. The formulation is simple, and the duration and release rate of stable drug release can be precisely controlled without the need for a barrier coating. For example, stable drug release can be controlled over 16 to 24 hours, with a 24-hour release rate exceeding 90%.

[0145] In some embodiments, an osmotic pump controlled-release preparation is provided, comprising the following structures arranged in sequence from inside to outside:

[0146] a tablet core comprising a drug-containing layer and a push-on layer;

[0147] a controlled-release coating layer with drug-releasing holes; and

[0148] An optional water-soluble coating film (the water-soluble coating film can serve as a moisture-proof coating film and / or an aesthetic coat, that is, can serve as at least one of a moisture-proof coating film and an aesthetic coat);

[0149] The drug-releasing hole connects the drug-containing layer and the outside of the osmotic pump controlled-release preparation; the booster layer is located on the side of the drug-containing layer away from the drug-releasing hole;

[0150] The drug-containing layer is composed of a pharmaceutical active ingredient, a hydrophilic polymer carrier and a pharmaceutical excipient F1; wherein the pharmaceutical excipient F1 is a pharmaceutical excipient different from the hydrophilic polymer carrier;

[0151] The boost layer is composed of a permeation-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure enhancer and a pharmaceutical excipient F2; wherein the permeation-promoting polymer comprises hydroxyethyl cellulose and alginate; the water-insoluble swelling polymer comprises one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone; wherein the pharmaceutical excipient F2 is a pharmaceutical excipient different from the permeation-promoting polymer, the water-insoluble swelling polymer and the osmotic pressure enhancer.

[0152] It should be understood that the portion of the controlled release coating layer adjacent to the push layer is not provided with drug release holes.

[0153] The osmotic pump controlled-release preparation can control the stable release of drugs within 16 to 24 hours, and the release rate at the 24-hour point can be greater than 90%. It can achieve clinical therapeutic effects at a frequency of once-daily administration, and the therapeutic effect of each administration can last for 24 hours.

[0154] In some embodiments, the structure of an osmotic pump controlled-release preparation can be seen in Figure 1 , where A and B correspond to osmotic pump controlled-release tablets with different numbers of release holes. The osmotic pump controlled-release preparations shown in Figures A and B in Figure 1 comprise, arranged from the inside out, the following structure: a core tablet comprising a drug-containing layer 1 and a push layer 2; and a controlled-release coating layer 3 with drug-releasing holes 4. The drug-releasing holes 4 connect the drug-containing layer 1 to the exterior of the osmotic pump controlled-release preparation; and the push layer 2 is located on the side of the drug-containing layer away from the drug-releasing holes 4.

[0155] In some embodiments, the structure of an osmotic pump controlled-release preparation can be seen in Figure 2 , which includes an osmotic pump controlled-release tablet with a water-soluble coating. The osmotic pump controlled-release preparation shown in Figure 2 includes the following structure, arranged from inside to outside: a tablet core comprising a drug-containing layer 1 and a push layer 2, a controlled-release coating layer 3 with a drug-releasing aperture 4, and a water-soluble coating 5. The drug-releasing aperture 4 connects the drug-containing layer 1 to the exterior of the osmotic pump controlled-release preparation; the push layer 2 is located on the side of the drug-containing layer away from the drug-releasing aperture 4.

[0156] In some embodiments, based on the total weight of the drug-containing layer, nifedipine accounts for 4% to 33% of the weight of the drug-containing layer, the hydrophilic polymer carrier accounts for 40% to 96% (optionally 40% to 95%, alternatively 40% to 94%, alternatively 65% ​​to 96%, alternatively 65% ​​to 94%, alternatively 65% ​​to 85%) of the weight of the drug-containing layer, and the pharmaceutical excipient F1 accounts for 0 to 2% of the weight of the drug-containing layer;

[0157] Based on the total weight of the push layer, the penetration-promoting polymer accounts for 11% to 66% by weight of the push layer (optionally 12% to 65%, alternatively 20% to 65%, alternatively 11% to 50%, alternatively 20% to 50%, and alternatively 20% to 40%), the water-insoluble swellable polymer accounts for 12% to 71% by weight of the push layer (optionally 13% to 70%, further optionally 15% to 60%, further optionally 20% to 50%, and further optionally 20% to 40%), the osmotic pressure enhancer accounts for 10% to 45% by weight of the push layer (optionally 14% to 42%, further optionally 15% to 40%), and the pharmaceutical excipient F2 accounts for 0.5% to 2.5% by weight of the push layer;

[0158] The weight ratio of the drug-containing layer to the booster layer is 0.5-2, optionally 0.8-1.6, further optionally 0.8-1.5, further optionally 0.9-1.5;

[0159] The weight gain of the controlled-release coating layer with drug-releasing holes is 6% to 25% of the weight of the tablet core, optionally 6% to 21%, further optionally 8% to 25%, further optionally 8% to 15%, further optionally 10% to 20%.

[0160] Chip

[0161] In some embodiments, the core tablet comprises a drug-containing layer and a push layer.

[0162] In some embodiments, the tablet core is composed of a drug-containing layer and a booster layer. In this case, the tablet core has a double-layer tablet core structure.

[0163] In some embodiments, the drug-containing layer and the push-in layer constitute a double-layer tablet core, as shown in FIG1 .

[0164] In some embodiments, the weight ratio of the drug-containing layer to the push layer is 0.5 to 2. The weight ratio of the drug-containing layer to the push layer can also be selected from any one of the following values ​​or any two intervals: 0.6, 0.7, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.7, 1.8, 1.9, etc. The weight ratio of the drug-containing layer to the push layer can also be selected from 0.8 to 1.6, 0.8 to 1.5, 0.9 to 1.5, 0.9 to 1.6, etc.

[0165] In some embodiments, the penetration-promoting polymer comprises hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer is any one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, or a combination thereof.

[0166] In some embodiments, the penetration-promoting polymer is hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer includes at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone.

[0167] In some embodiments, the penetration-promoting polymer is hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer is any one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, or a combination thereof.

[0168] In some embodiments, the penetration-promoting polymer comprises hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer is any one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, or a combination thereof.

[0169] In some embodiments, the penetration-promoting polymer is hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer includes at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0170] In some embodiments, the penetration-promoting polymer is hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer is any one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose or a combination thereof.

[0171] In some embodiments, the alginate in the permeation-enhancing polymer may be selected from one or more of sodium alginate, potassium alginate, and ammonium alginate.

[0172] Drug-containing layer

[0173] The drug-containing layer is a structural layer containing the active pharmaceutical ingredient.

[0174] In some embodiments, the drug-containing layer is composed of a pharmaceutically active ingredient, a hydrophilic polymer carrier, and a pharmaceutical excipient F1; further, the pharmaceutical excipient F1 is a pharmaceutical excipient different from the hydrophilic polymer carrier.

[0175] In some embodiments, based on the total weight of the drug-containing layer, the active pharmaceutical ingredient accounts for 4% to 33% of the weight of the drug-containing layer, the hydrophilic polymer carrier accounts for 40% to 96% of the weight of the drug-containing layer (optionally 40% to 95%, alternatively 40% to 94%, alternatively 65% ​​to 96%, alternatively 65% ​​to 94%, alternatively 65% ​​to 85%), and the pharmaceutical excipient F1 accounts for 0 to 2% of the weight of the drug-containing layer.

[0176] In some embodiments, based on the total weight of the drug-containing layer, the pharmaceutically active ingredient accounts for 4% to 33% of the weight of the drug-containing layer, and can also be selected from any one of the following percentages or any two intervals: 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, etc., and can also be selected from 4% to 30%, 4% to 25%, 4% to 20%, 5% to 30%, 5% to 25%, 5% to 20%, 7% to 30%, 7% to 25%, 7% to 20%, 8% to 30%, 8% to 25%, 8% to 20%, etc.

[0177] The amount of hydrophilic polymer carrier used in the drug-containing layer depends on the composition of the tablet core and the required drug release characteristics. In some embodiments, based on the total weight of the drug-containing layer, the hydrophilic polymer carrier accounts for 40% to 96% of the weight of the drug-containing layer, and can also be selected from any one or two of the following percentages: 65%, 66%, 67%, 68%, 69%, 70%, 72%, 74%, 75%, 76%, 78%, 80%, 82%, 84%, 85%, 86%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, 156%, 157%, 158%, 159%, 160%, 161%, 162 4%, 95%, etc., and can also be selected from 40% to 95%, 40% to 94%, 65% to 96%, 65% to 94%, 65% to 85%, 65% to 95%, 65% to 90%, 65% to 80%, 70% to 96%, 70% to 95%, 70% to 94%, 70% to 90%, 75% to 96%, 75% to 95%, 75% to 94%, 75% to 90%, 75% to 80%, etc.

[0178] In some embodiments, based on the total weight of the drug-containing layer, the pharmaceutical excipient F1 accounts for 0-2% of the weight of the drug-containing layer, and can also be selected from any one of the following percentages or any two intervals: 0.3%, 0.33%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1 .35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, 2%, etc., and can also be selected from 0.2% to 2%, 0.3% to 2%, 0.33% to 2%, 0.3% to 1.6%, 0.3% to 1%, 0.4% to 1%, 0.3% to 0.9%, 0.4% to 0.9%, 0.3% to 0.8%, 0.4% to 0.8%, etc.

[0179] In some embodiments, the pharmaceutically active ingredient is selected from any one of nifedipine, glipizide, oxybutynin hydrochloride, doxazosin mesylate, and paliperidone.

[0180] In some embodiments, the pharmaceutically active ingredient is nifedipine.

[0181] In some embodiments, in the drug-containing layer, the hydrophilic polymer carrier may include but is not limited to povidone, copovidone, or a combination thereof. In some embodiments, in the drug-containing layer, the hydrophilic polymer carrier is povidone, copovidone, or a combination thereof.

[0182] In some embodiments, in the drug-containing layer, the hydrophilic polymer carrier may include, but is not limited to, povidone K90, copovidone VA64, or a combination thereof. In some embodiments, in the drug-containing layer, the hydrophilic polymer carrier is povidone K90, copovidone VA64, or a combination thereof. In some embodiments, in the drug-containing layer, the hydrophilic polymer carrier is a combination of copovidone VA64 and povidone K90.

[0183] The drug-containing layer may also contain other drug-containing layer excipients available in the art (referred to as pharmaceutical excipients F1). In the present application, "pharmaceutical excipient F1" refers to a pharmaceutical excipient in the drug-containing layer that is different from the hydrophilic polymer carrier. In the present application, pharmaceutical excipient F1 may include, but is not limited to, one or more of a penetration enhancer, an antistatic agent, and a lubricant.

[0184] In some embodiments, the pharmaceutical excipient F1 is selected from one or more of an osmotic agent, an antistatic agent, and a lubricant.

[0185] In some embodiments, in the drug-containing layer, the penetration enhancer is selected from one or more of sodium chloride, potassium chloride, sorbitol, xylitol, glucose and sucrose, and may further be sodium chloride.

[0186] In some embodiments, in the drug-containing layer, the antistatic agent includes one or more of micro-powder silica gel, stearic acid, and polyethylene glycol, and may further be micro-powder silica gel.

[0187] In some embodiments, in the drug-containing layer, the lubricant is selected from one or more of magnesium stearate, polyethylene glycol, sodium stearyl fumarate, and talc. In some embodiments, in the drug-containing layer, the lubricant is selected from one or more of magnesium stearate, polyethylene glycol, and sodium stearyl fumarate.

[0188] booster layer

[0189] The boost layer, a layer of polymeric sustained-release material with its own expansion and propulsion effects, can assist in boosting and regulating the release rate. The boost layer of this application typically contains one or more sustained-release polymers, an osmotic pressure enhancer, and other boost layer excipients. The sustained-release polymer in the boost layer is an important component of osmotic pump controlled-release formulations and, in this application, typically contains a permeation-enhancing polymer and an insoluble swelling polymer.

[0190] In some embodiments, the push-boost layer is composed of a permeation-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure enhancer, and a pharmaceutical excipient F2; further, the permeation-promoting polymer comprises hydroxyethyl cellulose and alginate; further, the water-insoluble swelling polymer comprises one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone; further, the pharmaceutical excipient F2 is a pharmaceutical excipient different from the permeation-promoting polymer, the water-insoluble swelling polymer, and the osmotic pressure enhancer.

[0191] The permeation-enhancing polymer in the push-boost layer of this application is a key component in achieving controlled expansion of the push-boost layer. Traditionally, permeation-enhancing polymers typically include carbomer, polyoxyethylene, povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, or a combination thereof. Carbomer and polyoxyethylene are the most commonly used permeation-enhancing polymers in the push-boost layer of commercially available controlled-release osmotic pump formulations. However, the inventors of this application discovered that polyoxyethylene, due to its low melting point, is prone to "curling" due to heat generation during high-speed tableting. This raised "curling" can easily lead to weak spots in the coating film after coating, potentially causing drug burst release and safety risks. The inventors of this application also discovered that carbomer, due to its strong electrostatic interaction, is prone to powder agglomeration, agglomeration during granulation, and difficulty in mixing with other excipients. This makes tablet uniformity control during production difficult, and poses some issues with the stability of the final product's release rate. The inventors of this application have discovered through experimental exploration that if the above-mentioned penetration-promoting polymer is used in combination with an insoluble swelling polymer, the granulation and tableting processes have many disadvantages and high production requirements. Unevenly mixed products can easily lead to incomplete release (such as the final release amount <90%); or it is necessary to improve the release by adding an isolation coating film, which increases the preparation process, production cycle and production cost.

[0192] After extensive research and exploration, the inventors of the present application unexpectedly discovered in the process of studying the expansion mechanism of the booster layer that alginate (such as sodium alginate) and hydroxyethyl cellulose are used as the main permeation-promoting polymeric excipients, and are combined with insoluble swelling polymers (one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, etc.) and osmotic pressure enhancers to construct a booster layer composition, which is then combined with the drug-containing layer to form a tablet core. The components cooperate with each other and act synergistically. The osmotic pump controlled-release preparation prepared in this way can achieve complete release within 16 to 24 hours (final release amount >90%), and can achieve complete drug release for 24 hours (release rate >90%) without the need for an isolation coating membrane; in addition, when the booster layer is prepared using the above composition, there is no or basically no agglomeration phenomenon during the preparation, mixing or tableting process, the tablet mixing uniformity is good, and the production process quality controllability is good.

[0193] In some embodiments, based on the total weight of the push layer, the penetration-promoting polymer accounts for 11% to 66% of the weight of the push layer (optionally 12% to 65%, alternatively 20% to 65%, alternatively 11% to 50%, alternatively 20% to 50%, and alternatively 20% to 40%), the water-insoluble swelling polymer accounts for 12% to 71% of the weight of the push layer (optionally 13% to 70%, further optionally 15% to 60%, further optionally 20% to 50%, and further optionally 20% to 40%), the osmotic pressure enhancer accounts for 10% to 45% of the weight of the push layer (optionally 14% to 42%, further optionally 15% to 40%), and the pharmaceutical excipient F2 accounts for 0.5% to 2.5% of the weight of the push layer.

[0194] In some embodiments, based on the total weight of the push-boost layer, the penetration-promoting polymer accounts for 11% to 66% of the weight of the push-boost layer, and can also be selected from any one of the following percentages or any two intervals: 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, etc., and can also be selected from a suitable range of 11% to 50%, 11% to 40%, 12% to 65%, 20% to 65%, 11% to 50%, 20% to 50%, 20% to 40%, etc.

[0195] In some embodiments, in the push-boost layer, the penetration-promoting polymer mainly comprises hydroxyethyl cellulose and alginate. The "mainly comprising" means that the weight ratio meets greater than 80%. That is, in the push-boost layer, the weight ratio of the sum of the weight of hydroxyethyl cellulose and alginate (such as sodium alginate) in the penetration-promoting polymer is greater than 80%. In some embodiments, the weight ratio of the sum of the weight of hydroxyethyl cellulose and alginate (such as sodium alginate) in the penetration-promoting polymer can also be greater than 85%, greater than 90%, greater than 92%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, equal to 100%, etc.

[0196] In some embodiments, the alginate in the permeation-enhancing polymer may be selected from one or more of sodium alginate, potassium alginate, and ammonium alginate.

[0197] The inventors of this application speculate that the mechanism is as follows: based on the interaction between the molecular chains of alginate (such as sodium alginate) and the macromolecular chains of hydroxyethyl cellulose, the combination of hydroxyethyl cellulose and alginate (such as sodium alginate) can form a new three-dimensional network hydrogel system with both high strength and high toughness, thereby improving the mechanical properties of the booster layer composition (including good compressibility and tensile properties). The high-strength hydrogel formed can synergistically promote the uniform release of the active ingredients in the drug-containing layer of this product, increase the final release amount of the drug, and help to achieve complete release of the drug.

[0198] In some embodiments, in the push layer, the penetration-promoting polymer is composed of hydroxyethyl cellulose and alginate. The viscosity range of the alginate that can be used for the present application can be selected from, but is not limited to, 20cps to 1000cps, such as the interval consisting of any one or two of the following viscosity values: 20cps, 50cps, 60cps, 70cps, 75cps, 80cps, 90cps, 100cps, 110cps, 120cps, 130cps, 140cps, 143cps, 145cps, 150cps, 200cps, 250cps, 300cps, 350cps, 400cps, 500cps, 600cps, 700cps, 800cps, 900cps, 1000cps, etc. The viscosity of the alginate useful in the present application may be selected from a suitable range among the following ranges: 100 cps to 1000 cps, 100 cps to 800 cps, 100 cps to 700 cps, 140 cps to 650 cps, 140 cps to 600 cps, 143 cps to 600 cps, and the like.

[0199] In some embodiments, the alginate in the permeation-enhancing polymer is sodium alginate.

[0200] In some embodiments, in the push-assist layer, the penetration-enhancing polymer consists of hydroxyethyl cellulose and sodium alginate.

[0201] The alginate used in this application (such as sodium alginate) is a natural product generated by alginic acid and minerals in seawater. Its main source is kelp or giant kelp in brown algae, and it is a mixed polysaccharide structure composed of mannuronic acid (M) and guluronic acid (G). After alginate is dissolved in water, it can rapidly undergo ion exchange when encountering calcium ions to form a gel, and its gel is thermally irreversible. The gel generated by high-G type alginate is hard but brittle; the gel generated by high M type alginate is the opposite, with good flexibility but low hardness. Adjusting the two ratios can produce gels of different strengths.

[0202] The sodium alginate used in this application can be used in food and medicine and has good safety. The viscosity range of the sodium alginate that can be used in this application can be selected from, but is not limited to, 20 cps to 1000 cps, for example, any one or two of the following viscosity values: 20 cps, 50 cps, 60 cps, 70 cps, 75 cps, 80 cps, 90 cps, 100 cps, 110 cps, 120 cps, 130 cps, 140 cps, 143 cps, 145 cps, 150 cps, 200 cps, 250 cps, 300 cps, 400 cps, 500 cps, 600 cps, 700 cps, 800 cps, 900 cps, 1000 cps, etc. The viscosity of the sodium alginate used in the present application can be selected from the following suitable ranges: 100 cps to 1000 cps, 100 cps to 800 cps, 100 cps to 700 cps, 140 cps to 650 cps, 140 cps to 600 cps, 143 cps to 600 cps, etc. The sodium alginate in the booster layer of the present application slowly swells in water to form a highly viscous gel, which helps control the swelling rate of the insoluble polymer and achieve uniform release.

[0203] Potassium alginate, as used herein, is a milky white to light yellow powder or granules with excellent hydrophilicity, fluidity, thickening, and gelling properties. Its strength is superior to that of sodium alginate under the same conditions. As a hydrophilic colloid, it readily dissolves in water to form a viscous solution. Potassium alginate, as used herein, can be used in one or more aspects of food, health products, and pharmaceuticals. The viscosity range of potassium alginate used in the present application can be selected from, but not limited to, 20 cps to 1000 cps, for example, any one or two of the following viscosity values: 20 cps, 50 cps, 60 cps, 70 cps, 75 cps, 80 cps, 90 cps, 100 cps, 110 cps, 120 cps, 130 cps, 140 cps, 143 cps, 145 cps, 150 cps, 200 cps, 250 cps, 300 cps, 400 cps, 500 cps, 600 cps, 700 cps, 800 cps, 900 cps, 1000 cps, etc. The viscosity of potassium alginate that can be used in the present application can be selected from a suitable range among the following ranges: 100 cps to 1000 cps, 100 cps to 800 cps, 100 cps to 700 cps, 140 cps to 650 cps, 140 cps to 600 cps, 143 cps to 600 cps, and the like.

[0204] Ammonium alginate used in the application is a light yellow to brown amorphous powder or granule, has good hydrophilicity, thickening property, gel property, as hydrophilic colloid, is soluble in water and forms viscous solution.The potassium alginate used in this product can be used for one or more aspects in food, health products and medicine.The viscosity range that can be used for the ammonium alginate of the application can be selected from but not limited to 20cps to 800cps, such as the interval consisting of any one of the following viscosity values ​​or any two viscosity values: 20cps, 50cps, 60cps, 70cps, 75cps, 80cps, 90cps, 100cps, 110cps, 120cps, 130cps, 140cps, 143cps, 145cps, 150cps, 200cps, 250cps, 300cps, 400cps, 500cps, 600cps, 700cps, 800cps etc. The viscosity of the ammonium alginate that can be used in the present application can be selected from a suitable range among the following ranges: 100 cps to 800 cps, 100 cps to 700 cps, 140 cps to 650 cps, 140 cps to 600 cps, 143 cps to 600 cps, and the like.

[0205] The hydroxyethyl cellulose used in this application is a nonionic, water-soluble polymer material that absorbs water and rapidly swells. Hydroxyethyl cellulose rapidly gels upon contact with water. Hydroxyethyl cellulose is commonly used in pharmaceutical formulations as a tablet binder, matrix material, and film coating material. However, there has been no research on its use as a permeation-enhancing polymer in a push-boost layer. The inventors of this application serendipitously discovered the use of hydroxyethyl cellulose in the push-boost layer and achieved surprisingly positive results.

[0206] In some embodiments, in the boost layer, the weight ratio of hydroxyethyl cellulose to alginate (such as sodium alginate) is 1:(1-60), further 1:(1.5-40), further 1:(1.5-25), further 1:(1.5-20), and further 1:(1.5-16). In the boost layer, the weight ratio of hydroxyethyl cellulose to alginate (such as sodium alginate) can also be selected from the following ranges consisting of any one or any two of the following: 1:1.5, 1:1.8, 1:2, 1:5, 1:6, 1:8, 1:10, 1:15, 1:16, 1:20, 1:25, 1:30, 1:35, 1:40, 1:50, etc.

[0207] In some embodiments, the weight proportion of hydroxyethyl cellulose in the boost layer is 0.4% to 22%, further 0.5 to 20%, and can also be selected from any one of the following percentages or any two intervals: 0.4%, 0.5%, 0.6%, 0.8%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc. The weight proportion of hydroxyethyl cellulose in the boost layer can also be 0.4% to 22%, further 0.5 to 20%, and can also be selected from any one of the following percentages or any two intervals: 0.4%, 0.5%, 0.6%, 0.8%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc. In any appropriate range selected from the following ranges: 1% to 22%, 1% to 20%, 2% to 22%, 2% to 20%, 2.5% to 22%, 2.5% to 20%, 4% to 22%, 4% to 20%, 5% to 22%, 5% to 20%, 0.5% to 15%, 1% to 15%, 2% to 15%, 2.5% to 15%, 4% to 15%, 5% to 15%, 0.5% to 10%, 1% to 10%, 2% to 10%, 2.5% to 10%, 4% to 10%, 5% to 10%, etc.

[0208] In some embodiments, the boost layer satisfies one or more of the following characteristics:

[0209] In the boosting layer, the weight ratio of hydroxyethyl cellulose to alginate (such as sodium alginate) is 1:(1-60), further 1:(1.5-40), further 1:(1.5-25), further 1:(1.5-20), further 1:(1.5-16), and reference may also be made to the appropriate ranges or values ​​in the aforementioned weight ratios;

[0210] In the boosting layer, the weight proportion of hydroxyethyl cellulose in the boosting layer is 0.4% to 22% (or further can be 0.5 to 20%), and reference can also be made to the appropriate value or range of the weight proportion mentioned above.

[0211] In one embodiment of the present application, an osmotic polymer combination of alginate (such as sodium alginate) and hydroxyethyl cellulose provides a permeation-promoting polymer, which achieves more than 90% release within 24 hours without the need for an isolation coating membrane; in another embodiment (such as Preparation Example Prescription 2 and Experimental Example 4), a controlled-release tablet prepared using the osmotic polymer combination of alginate (which may further be sodium alginate) and hydroxyethyl cellulose in the present application, compared to hypromellose K15M and / or copovidone (one or a combination of the two), the final release amount of the drug in the technical solution provided in the present application is more complete, such as the release rate of the tablet of Preparation Example Prescription 2 at the 24-hour point is 102.7%, while the 24-hour release rate of the tablet of Preparation Example Comparative Prescription 1 (a combination of hypromellose K15M and copovidone) is only 86.7%.

[0212] In the present application, hydroxyethyl cellulose can also increase the adhesion between the auxiliary material particles of the tablet. The addition of hydroxyethyl cellulose makes the prepared osmotic pump controlled-release preparation (such as a double-layer tablet) have good compressibility, which is conducive to achieving high-speed tableting and improving production efficiency.

[0213] The insoluble swelling polymer in the boosting layer of the present application can swell rapidly when it comes into contact with water, thereby boosting the release of the drug.

[0214] In some embodiments, based on the total weight of the push layer, the water-insoluble swellable polymer accounts for 12% to 71% by weight of the push layer, and can also be selected from any one of the following percentages or any two intervals: 13%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, etc., and can also be selected from 12% to 60%, 12% to 50%, 12% to 40%, 13% to 70%, 13% to 60%, 13% to 50%, 13% to 40%, 15% to 70%, 15% to 60%, 15% to 50%, 15% to 40%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, etc.

[0215] In some embodiments, the water-insoluble swelling polymer includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone.

[0216] In some embodiments, the water-insoluble swelling polymer is any one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, or a combination thereof; "combination thereof" means any suitable combination of the aforementioned water-insoluble swelling polymers.

[0217] In some embodiments, the water-insoluble swelling polymer includes at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose. Further, the water-insoluble swelling polymer may also optionally include one or more of cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone.

[0218] In some embodiments, the water-insoluble swelling polymer includes sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0219] In some embodiments, the water-insoluble swelling polymer is a combination of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0220] In the present application, "low-substituted hydroxypropyl cellulose" can be prepared by reacting alkaline cellulose with propylene oxide under high temperature and high pressure. The hydroxypropyl substitution rate can be 5% to 16%, and further, for example, 7% to 16%.

[0221] The booster layer of the present application contains an osmotic pressure enhancer. Osmotic pressure enhancers (such as inorganic salt osmotic pressure enhancers such as sodium chloride) may affect the viscosity of some polymer materials, increase the polarity of the solution, compress the macromolecular double layer, and cause the macromolecular chains to become curled, resulting in a decrease in viscosity. The viscosity of the hydroxyethyl cellulose used in this application is not affected by the sodium chloride content and has good salt resistance. This ensures that the hydroxyethyl cellulose forms a stable gel system after absorbing water in the gastrointestinal tract, which can achieve a smooth release of the drug.

[0222] In some embodiments, based on the total weight of the push layer, the osmotic pressure enhancer accounts for 10% to 45% by weight of the push layer, further 14% to 42%, further 15% to 40%, further 15% to 35%, further 15% to 30%. It can also be selected from any one or any two of the following percentages: 15%, 16%, 18%, 20%, 25%, 30%, 35%, 36%, 38%, 40%, 41%, etc.

[0223] In some embodiments, in the boost layer, the osmotic pressure enhancer is an inorganic salt osmotic pressure enhancer, and may further be sodium chloride.

[0224] In some embodiments, in the boost layer, the osmotic pressure enhancer is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, sorbitol, xylitol, glucose and sucrose, and may further be sodium chloride.

[0225] In some embodiments, the osmotic pressure enhancer in the boost layer is sodium chloride. As an osmotic pressure enhancer, sodium chloride has stable physical and chemical properties, good water solubility, and good biosafety.

[0226] In the present application, the push layer may also contain other push layer excipients available in the art (referred to as pharmaceutical excipient F2). In the present application, "pharmaceutical excipient F2" refers to the same pharmaceutical excipient as the hydrophilic polymer carrier in the push layer. In the present application, pharmaceutical excipient F2 may include, but is not limited to, one or more of lubricants, colorants, and the like.

[0227] In some embodiments, in the push layer, the pharmaceutical excipient F2 is selected from one or more of a lubricant, a colorant, and a glidant.

[0228] In some embodiments, based on the total weight of the push layer, the pharmaceutical excipient F2 accounts for 0.5% to 2.5% by weight of the push layer, further 0.5% to 2%, and further such as 0.5% to 1.5%. It can also be selected from any one or any two of the following percentages: 0.5%, 0.6%, 0.7%, 8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, etc.

[0229] The addition of a lubricant can improve the flowability of the granules in the drug-containing layer and the push layer during high-speed tableting, thereby improving the content and content uniformity of the drug preparation. The lubricant in the push layer can be selected from, but is not limited to, one or more of stearic acid, magnesium stearate, sodium stearyl fumarate, talc, and paraffin.

[0230] The use of a colorant can make it easier to distinguish between the drug-containing layer and the booster layer. The choice of color does not affect the actual use and effect of the present invention. The colorant in the booster layer can be selected from, but not limited to, one or more of iron oxide red, iron oxide yellow, iron oxide purple, and iron oxide black.

[0231] The use of flow aids is mainly to improve the fluidity of powders or granules, which is beneficial to the stable control of the tableting process. The range of flow aids in the push layer includes but is not limited to micro powder silica gel.

[0232] In some embodiments, a barrier film is not included between the core tablet and the controlled-release coating layer. In some embodiments, a barrier film is not included between the drug-containing layer and the booster layer. The osmotic pump controlled-release formulation provided herein can achieve a high drug release rate (over 90% release at 24 hours) without the use of a barrier film.

[0233] In some embodiments, the push-up layer does not contain polyethylene oxide, which can overcome the thermal sensitivity of polyethylene oxide in traditional push-up layers.

[0234] In some embodiments, the push layer does not contain carbomer, which can avoid defects such as unstable release between tablets caused by uneven mixing and granulation.

[0235] In the present application, the components of the drug-containing layer and the components of the booster layer can be pressed into a tablet core using a mold, such as a double-layer tablet core structure.

[0236] Controlled release coating with drug release holes

[0237] In this application, the controlled release coating layer, also known as the controlled release coating membrane, is a key component of the osmotic pump controlled release composition. The presence of the controlled release coating membrane allows water to permeate through, while the permeation enhancer and osmotic polymer cannot pass through, thereby ensuring a relatively independent microenvironment inside the tablet core.

[0238] In some embodiments, the weight gain of the controlled release coating layer with drug release holes is 6% to 25% of the weight of the tablet core, optionally 6% to 21%, alternatively 8% to 25%, alternatively 8% to 15%, alternatively 10% to 20%. It can also be selected from any one or any two of the following percentages: 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, etc.

[0239] In some embodiments, the controlled-release coating layer with drug-releasing holes mainly comprises cellulose acetate or a premixed coating powder containing cellulose acetate (such as Opadry CA), but is not limited thereto.

[0240] In some embodiments, the controlled release coating layer with drug release holes is composed of a semipermeable controlled release coating membrane material and an optional controlled release coating layer excipient (denoted as pharmaceutical excipient F3); further, pharmaceutical excipient F3 can be a plasticizer and / or a pore-forming agent, pharmaceutical excipient F3 can be a plasticizer, a pore-forming agent, or a combination of a plasticizer and a pore-forming agent.

[0241] In some embodiments, the semipermeable controlled-release coating material is cellulose acetate or a premixed coating powder containing cellulose acetate.

[0242] In the controlled release coating layer of the present application, the pore-forming agent and / or plasticizer can increase the water permeability of the controlled release coating film material.

[0243] In some embodiments, based on the total weight of the controlled-release coating, the pharmaceutical excipient F3 is a plasticizer and / or a pore-former (i.e., one or a combination of a plasticizer and a pore-former), and the weight proportion of the pharmaceutical excipient F3 in the dry coating is 0-20%, further 1-10%, further 1%-7.4%, and further 1-7%. It can also be selected from the following percentages or any two intervals: 0.2%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, 1%, 1.2%, 1.4%, 1.5%, 1.6%, 1.8%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 7.2%, 7.4%, 7.5%, 7.6%, 7.8%, 8%, 8.5%, 9%, 10%, 12%, 15%, 16%, 18%, etc. It can also be selected from 0.5% to 20%, 0.5% to 10%, 0.5% to 8%, 0.5%~7.5%, 0.5%~7.4%, 0.5%~7%, 0.6%~20%, 0.6%~10%, 0.6%~8%, 0.6%~7.5%, 0.6%~7.4%, 0.6%~7%, 0.8%~20%, 0.8%~10%, 0.8%~8%, 0.8%~7.5%, 0.8%~7.4%, 0.8%~7%, 0.9%~20%, 0.9%~10%, 0.9%~8%, 0.9%~7.5%, 0.9%~7.4%, 0.9%~7%, etc.

[0244] In this application, the "dried film" of a controlled release coating refers to the coating formed after dissolving the controlled release coating material and F3 excipient in a solvent, coating the tablet core, and then drying to remove the solvent. The main components of the "dried film" of the controlled release coating are the semipermeable controlled release coating material and F3 excipient.

[0245] In some embodiments, the dry controlled-release coating of the controlled-release coating is composed of a semipermeable controlled-release coating material and a pharmaceutical excipient F3. In this case, the weight ratio of the pharmaceutical excipient F3 to the sum of the weights of the semipermeable controlled-release coating material and the pharmaceutical excipient F3 can be 0-20%, further 1-10%, further 1-7.4%, and further 1-7%. The weight ratio of the pharmaceutical excipient F3 in the dry coating can also be selected from any suitable percentages described above.

[0246] In some embodiments, the pore-forming agent used in the controlled release coating layer can be selected from, but not limited to, glycerol, povidone, copovidone, propylene glycol, polyethylene glycol, and the like.

[0247] The plasticizer used in the controlled release coating layer of the present application can make the controlled release coating film have better flexibility and stretchability.

[0248] In some embodiments, the pharmaceutical excipient F3 is selected from one or more of polyethylene glycol, diethyl phthalate, triethyl citrate, triacetin, dibutyl sebacate, and the like.

[0249] In some embodiments, when preparing a controlled release coating layer with drug release holes, the solvent suitable for the controlled release coating layer of the present application can be selected from but not limited to one or more of acetone, water, ethanol, methanol, isopropanol and dichloromethane.

[0250] In the present application, the controlled-release coating can be coated on the tablet core after being dried by spraying using a high-efficiency coating pan.

[0251] In some embodiments, the controlled release coating layer has at least one channel (which may be referred to as a drug release hole) connecting the drug-containing layer and the exterior, allowing the drug-containing layer to release the drug. In some embodiments, the drug release hole can be prepared by mechanical drilling or laser drilling.

[0252] In some embodiments, there are one or more drug release holes, and further, any one of the drug release holes communicates with the drug-containing layer and the outside of the osmotic pump controlled-release preparation.

[0253] In some embodiments, the diameter of any drug-releasing hole is 0.6-1.0 mm, with non-limiting examples such as 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, etc.

[0254] Optional film coating

[0255] Unless otherwise specified, the coating film in this application is a water-soluble coating film.

[0256] In the present application, the water-soluble coating film is an optional structure, which can be used as a moisture-proof coating film and / or an aesthetic coat, can be used as a moisture-proof coating film, can be used as an aesthetic coat, or can be used as both a moisture-proof coating film and an aesthetic coat.

[0257] The moisture-proof coating film and the aesthetic outer coat can be provided by the same water-soluble coating film or by different water-soluble coating films. The moisture-proof coating film and the aesthetic outer coat are provided separately, and in some embodiments, the aesthetic outer coat is located outside the moisture-proof coating film.

[0258] In this application, the moisture-proof coating membrane is an optional structure and may or may not be provided. When the moisture-proof coating membrane is provided, it can be stacked with the controlled release coating layer with drug release holes and located on the surface of the controlled release coating layer away from the drug-containing layer.

[0259] In this application, the aesthetic coat is an optional structure and may or may not be provided. When the aesthetic coat is provided, it may be stacked with the controlled release coat layer with drug release holes and located on the surface of the controlled release coat layer away from the drug-containing layer.

[0260] In some embodiments, the weight gain of the water-soluble coating is 8% to 20% of the combined weight of the core tablet and the controlled-release coating layer with drug-releasing apertures. The weight gain can also be selected from any one or two of the following percentages: 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, and the like. It can also be selected from 10% to 20%, 10% to 18%, and the like. In the present application, the water-soluble coating can improve the appearance of the formulation to increase patient compliance and provide color identification. The components of the water-soluble coating can be selected from one or more of a colorant, a plasticizer, a sunscreen, an anti-adherent agent, a solvent, and the like.

[0261] In some embodiments, the moisture-proof coating film may include Opadry, Sepinlan, and other coating powders known to those skilled in the art that can form a moisture-proof coating.

[0262] In some embodiments of the present application, the controlled release coating layer and the water-soluble coating film are stacked in sequence, as shown in Figure 2. In some embodiments, the weight gain of the water-soluble coating film is 5-20% of the sum of the weight of the tablet core and the controlled release coating layer with drug release holes.

[0263] Release properties

[0264] In some embodiments, the osmotic pump controlled-release formulation is controlled-released at 37° C. and 100 rpm, and the release behavior of the active pharmaceutical ingredient in the osmotic pump controlled-release formulation satisfies one or more of the following release properties:

[0265] The release rate at 4 hours was greater than 4%;

[0266] The release at the 12-hour point is greater than 40%; and

[0267] The release rate at 24 hours is greater than 90%;

[0268] Alternatively, the release medium can be 900 mL of 1% sodium lauryl sulfate phosphate-citrate buffer, 900 mL of artificial intestinal fluid without pancreatic enzymes, 500 mL of 0.1 mol / L hydrochloric acid solution, 900 mL of 0.1 mol / L hydrochloric acid solution, or 500 mL of 0.2% (w / v) sodium chloride 0.1 mol / L hydrochloric acid solution. The osmotic pump controlled-release preparation can contain any suitable pharmaceutical active ingredient as described above, including but not limited to any one or any combination of nifedipine, glipizide, oxybutynin hydrochloride, doxazosin mesylate, and paliperidone. In this case, the large fluctuations in blood drug concentration of ordinary oral preparations can be avoided, the number of medications can be reduced, and the safety, efficacy, and compliance of the drug can be improved. The "hydrochloric acid solution" here refers to a solution containing hydrochloric acid in water, and can optionally be a hydrochloric acid aqueous solution consisting of hydrochloric acid and water.

[0269] Furthermore, in some embodiments, the release behavior of the active pharmaceutical ingredient in the osmotic pump controlled-release formulation satisfies one or more of the following release properties:

[0270] The release rate at 4 hours was 4% to 40%;

[0271] The release rate at 12 hours is 40% to 85%; and

[0272] The release rate at 24 hours was greater than 90%.

[0273] In other embodiments, the release behavior of the active pharmaceutical ingredient in the osmotic pump controlled-release formulation satisfies one or more of the following release properties:

[0274] The release rate at 4 hours is 4% to 30%;

[0275] The release rate at 12 hours is 40% to 85%; and

[0276] The release rate at 24 hours was greater than 90%.

[0277] In other embodiments, the release behavior of the active pharmaceutical ingredient in the osmotic pump controlled-release formulation satisfies one or more of the following release properties:

[0278] The release rate at 4 hours is 4% to 20%;

[0279] The release rate at 12 hours is 40% to 80%; and

[0280] The release rate at 24 hours was greater than 90%.

[0281] In some embodiments, a 1% sodium dodecyl sulfate phosphate-citrate buffer medium is prepared as follows: 7.15% disodium hydrogen phosphate-2.1% citric acid (77.3:22.7 volume ratio v / v), pH = 6.8, and the buffer is diluted 10 times by volume before use (can be diluted with water).

[0282] The osmotic pump controlled-release preparation provided in the present application can release drugs at a constant release rate within a certain time range.

[0283] In some embodiments, using the active pharmaceutical ingredient nifedipine as an example, an osmotic pump controlled-release formulation in 900 mL of 1% sodium lauryl sulfate phosphate-citrate buffer at 37°C, paddle speed, and 100 rpm can achieve release rates of 4%-20%, 40%-80%, and >90% at 4, 12, and 24 hours, respectively. This avoids the large fluctuations in blood drug concentration associated with conventional oral formulations, reduces dosing frequency, and improves drug safety, efficacy, and compliance. See Figure 3.

[0284] In some embodiments, using glipizide as an example, an osmotic pump controlled-release formulation in 900 mL of pancreatic-free artificial intestinal fluid at 37°C, using a paddle system at 50 rpm, can achieve release rates of 4%-40%, 40%-85%, and >90% at 4, 12, and 24 hours, respectively. This avoids the large fluctuations in blood drug concentration associated with conventional oral formulations, reduces the frequency of dosing, and improves drug safety, efficacy, and compliance. See Figure 6.

[0285] In some embodiments, taking the active pharmaceutical ingredient oxybutynin hydrochloride as an example, an osmotic pump controlled-release formulation in 500 mL of 0.1 mol / L hydrochloric acid solution, at 37°C, using a paddle method at 50 rpm, can release 4%-20%, 40%-80%, and >90% of the drug at 4, 12, and 24 hours, respectively. This avoids the large fluctuations in blood drug concentration associated with conventional oral formulations, reduces the frequency of dosing, and improves drug safety, efficacy, and compliance. See Figure 7.

[0286] In some embodiments, using doxazosin mesylate as an active ingredient, an osmotic pump controlled-release formulation in 900 mL of 0.1 mol / L hydrochloric acid solution at 37°C, paddle speed, and 75 rpm can release 4%-30%, 40%-85%, and >90% of the drug at 4, 12, and 24 hours, respectively. This avoids the large fluctuations in blood concentration associated with conventional oral formulations, reduces the frequency of dosing, and improves drug safety, efficacy, and compliance. See Figure 8.

[0287] In some embodiments, taking paliperidone as an active pharmaceutical ingredient, an osmotic pump controlled-release formulation in 500 mL of a 0.2% (w / v) sodium chloride solution in 0.1 mol / L hydrochloric acid at 37°C, paddle speed, 50 rpm, can release 4%-30%, 40%-85%, and >90% of the drug at 4, 12, and 24 hours, respectively. This avoids the large fluctuations in blood drug concentration associated with conventional oral formulations, reduces the frequency of dosing, and improves drug safety, efficacy, and compliance. See Figure 9.

[0288] In the second aspect of the present application, an osmotic pump controlled-release composition is provided, which is composed of the components of the osmotic pump controlled-release preparation of the first aspect of the present application and can be used to prepare the osmotic pump controlled-release preparation of the first aspect of the present application.

[0289] In a third aspect of the present application, a method for preparing an osmotic pump controlled-release preparation is provided, which can be used to prepare the osmotic pump controlled-release preparation of the first aspect of the present application, and the preparation method comprises the following steps in sequence:

[0290] S100: preparing drug-containing layer granules according to the components of the drug-containing layer, and preparing booster layer granules according to the components of the booster layer;

[0291] S200: pressing the drug-containing layer particles and the booster layer particles into tablet cores in a mold;

[0292] S300: coating the outer surface of the tablet core with a controlled-release coating layer, and then punching holes in the controlled-release coating layer to form a controlled-release coating layer with drug-releasing holes;

[0293] S400: Optionally, coating with a water-soluble coating film.

[0294] Step S100 includes sub-steps S110 and S120. S110: Prepare drug-containing layer granules based on the components of the drug-containing layer; S120: Prepare booster layer granules based on the components of the booster layer. There is no order restriction between sub-steps S110 and S120.

[0295] In some embodiments, a method for preparing an osmotic pump controlled-release preparation is provided, comprising the following steps in sequence: ① preparing drug-containing layer particles and push-layer particles; ② pressing the drug-containing layer particles and the push-layer particles into a double-layer tablet core; ③ coating the outer surface of the tablet core with a controlled-release coating layer; ④ punching holes in the controlled-release coating layer to form drug-releasing holes connecting the drug-containing layer and the exterior; ⑤ optionally, coating the controlled-release coating layer with the drug-releasing holes with a water-soluble coating film (such as a moisture-proof coating film).

[0296] In some embodiments, a method for preparing an osmotic pump controlled-release formulation is provided, which comprises the following steps in order of the preparation processes: (1) preparing drug-containing composition particles; (2) preparing push-layer particles; (3) compressing a double-layer tablet core; (4) coating with a controlled-release coating; (5) punching the coated tablet; and (6) coating with a water-soluble coating film (if any).

[0297] In some embodiments, a method for preparing an osmotic pump controlled-release formulation is provided, comprising the following steps:

[0298] (1) Preparation of drug-layered granules

[0299] Keep out of light. Evenly mix the prescribed amount of drug (passed through a 60-mesh sieve) with the drug-containing layer excipients, add to the fluidized bed, and spray with an 80% ethanol-water solution for granulation. Stop granulation when the appropriate particle size is reached. Dry, pass through a 20-mesh sieve for granulation, add magnesium stearate, mix thoroughly, and set aside.

[0300] (2) Preparation of booster layer particles

[0301] After the prescribed amount of booster layer excipients passed through a 60-mesh sieve is mixed evenly, the mixture is added to a fluidized bed and the aqueous solution is sprayed in for granulation. When the particle size reaches an appropriate size, the granulation is stopped and the mixture is dried. The granules are passed through a 20-mesh sieve and magnesium stearate is added. The mixture is mixed evenly and set aside.

[0302] (3) Tablet pressing

[0303] The drug-containing layer and booster layer granules prepared above were added to the hopper of a double-layer tablet press and compressed into double-layer tablet cores of appropriate hardness using the double-layer tablet press. The hardness, content, and content uniformity of the double-layer tablet cores were measured.

[0304] (4) Controlled release coating

[0305] According to the prescription composition of the example, a controlled-release semipermeable membrane coating solution was prepared; the above-mentioned qualified double-layer tablet cores were coated with the controlled-release semipermeable membrane coating solution, and the coated products were dried at 50°C for 12 hours to remove excess organic solvent and moisture.

[0306] (5) Perforation of coated tablets

[0307] The coated tablets that have passed the above inspection are punched with a drug-releasing hole with a diameter of 0.6 to 1.0 mm on the surface of the drug-containing layer of the tablet using a laser puncher or mechanical means.

[0308] (6) Coated with a water-soluble coating, such as a moisture-proof coating (if any)

[0309] Disperse the coating powder (e.g., moisture-proof coating powder) in water and dissolve it to prepare a coating solution with a solid content of 5-15%. Place the perforated tablets in a high-efficiency coating pan and coat them with the prepared coating solution to the desired coating weight gain. Dry at 60°C for 2 hours to remove excess water to obtain an osmotic pump controlled-release preparation.

[0310] In the fourth aspect of the present application, a push layer composition is provided, which is composed of a permeation-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure enhancer and a pharmaceutical excipient F2; wherein,

[0311] The definitions of the penetration-promoting polymer, the water-insoluble swelling polymer, the osmotic pressure enhancer and the pharmaceutical excipient F2 are as defined in the first aspect of the present application.

[0312] In some embodiments, the penetration-promoting polymer is a combination of alginate and hydroxyethyl cellulose. The definition of alginate is as described above. In some embodiments, the alginate is sodium alginate.

[0313] The push layer composition provided in this application is composed of a specific permeation-promoting polymer (optionally a combination of alginate and hydroxyethyl cellulose, wherein the alginate is, for example, sodium alginate) and a suitable water-insoluble swelling polymer (including at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, and cross-linked polyvinylpyrrolidone, further including at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, further including sodium carboxymethyl starch and / or low-substituted hydroxypropyl cellulose, which may be sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, or a combination of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose), an osmotic pressure enhancer, and other push layer excipients (pharmaceutical excipient F2). The resulting high-strength and high-toughness hydrogel helps improve the mechanical properties of the push layer composition, promotes the release of drugs and excipients in the drug-containing layer at a controlled release rate through the drug release pores in the controlled-release coating layer, and can ensure the uniform release of the active ingredient in the drug-containing layer, thereby increasing the final release amount of the drug (24-hour point release >90%) and facilitating complete drug release. The booster layer composition can be applied to the preparation and controlled-release administration of a variety of active ingredients, including but not limited to glipizide, oxybutynin hydrochloride, doxazosin mesylate and paliperidone, and can achieve stable controlled release of the active ingredients in different dissolution media, and the drug release is complete.

[0314] Compared with traditional osmotic pump controlled-release tablets, the osmotic pump controlled-release preparation prepared using the aforementioned unexpectedly discovered push-layer composition also has the following beneficial effects: the excipients are stable and not easily aggregated during the preparation process, the release of the active ingredients in the product is more stable, and the release rate difference between tablets is small.

[0315] In a fifth aspect of the present application, there is provided use of the osmotic pump controlled-release preparation of the first aspect of the present application as an oral controlled-release preparation.

[0316] In some embodiments, the osmotic pump controlled-release formulation is an oral controlled-release tablet. Furthermore, the dosage is 200-1000 mg / tablet. The weight of each tablet can also be selected from any one or any two of the following ranges: 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, etc.

[0317] In the sixth aspect of the present application, there is provided the use of the osmotic pump controlled-release preparation of the first aspect of the present application, or the osmotic pump controlled-release composition of the second aspect of the present application, or the booster layer composition of the fourth aspect of the present application in the preparation of a drug for preventing and / or treating cardiovascular diseases, optionally, the active ingredient of the drug is nifedipine.

[0318] In this application, unless otherwise specified, "prevention and / or treatment of cardiovascular diseases" refers to at least one of prevention of cardiovascular diseases and treatment of cardiovascular diseases.

[0319] In some embodiments, the cardiovascular disease comprises at least one of hypertension and chronic stable angina pectoris (exertional angina pectoris) of coronary artery disease.

[0320] In some embodiments, the cardiovascular disease is hypertension or chronic stable angina pectoris of coronary artery disease.

[0321] In the seventh aspect of the present application, a method for preventing cardiovascular disease is provided, comprising administering to a subject a preventively effective amount of the osmotic pump controlled-release preparation described in the first aspect of the present application, or administering to a subject a preventively effective amount of the osmotic pump controlled-release composition described in the second aspect of the present application.

[0322] Optionally, the cardiovascular disease includes at least one of hypertension and chronic stable angina pectoris of coronary heart disease.

[0323] In the eighth aspect of the present application, a method for the treatment of cardiovascular disease is provided, comprising administering to a subject a therapeutically effective amount of the osmotic pump controlled-release preparation described in the first aspect of the present application, or administering to a subject a therapeutically effective amount of the osmotic pump controlled-release composition described in the second aspect of the present application.

[0324] Optionally, the cardiovascular disease includes at least one of hypertension and chronic stable angina pectoris of coronary heart disease.

[0325] In a ninth aspect of the present application, an osmotic pump controlled-release preparation for at least one of preventing and treating cardiovascular diseases is provided, wherein the osmotic pump controlled-release preparation is as defined in the first aspect of the present application.

[0326] In a tenth aspect of the present application, an osmotic pump controlled-release composition for at least one of preventing and treating cardiovascular diseases is provided, wherein the osmotic pump controlled-release composition is as defined in the first aspect of the present application.

[0327] In the seventh, eighth, ninth and tenth aspects of the present application, the definition of cardiovascular disease may be as defined in the sixth aspect of the present application.

[0328] In this application, unless otherwise specified, "prevention" of a disease refers to preventing the occurrence or development of a disease or condition.

[0329] In this application, unless otherwise specified, "treatment" of a disease means alleviating, delaying progression, attenuating, or maintaining an existing disease or condition. Treatment also includes curing one or more symptoms of a disease or condition, preventing its development, or alleviating it to a certain extent.

[0330] As used herein, "drug" includes any agent, compound, composition, or mixture that provides at least one of a physiological effect and a pharmacological effect in vivo or in vitro, often with a beneficial effect. The scope of the physiological effect and the scope of the pharmacological effect of a "drug" in vivo are not particularly limited, and each can independently produce a systemic effect or a localized effect.

[0331] In this application, a "subject" is an animal, preferably a mammal, and more preferably a human. Subjects include, but are not limited to, patients with at least one of the following diseases, conditions, and related symptoms, or potential patients. "Potential patients" are people who, while not yet diagnosed as "patients" due to the disease, condition, or related symptoms, are at risk of or have the potential to develop into a "patient."

[0332] In this application, unless otherwise specified, the term "mammal" mainly refers to warm-blooded vertebrate mammals, including but not limited to: cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice (such as rats, mice), pigs, cattle, sheep, horses, humans, etc., preferably primates, and more preferably humans.

[0333] In some embodiments of any of the foregoing aspects, the subject is a human or a dog.

[0334] In the present application, "patient" refers to an animal, preferably a mammal, such as a human or a dog.

[0335] In this application, unless otherwise specified, "prophylactically effective amount" refers to the amount of a pharmaceutical active ingredient that will cause a biological or medical response in an individual to the occurrence or development of at least one of a disease, disorder and related symptoms, for example, the amount of a pharmaceutical active ingredient that brings at least one positive effect physiologically and pharmacologically to an individual.

[0336] In this application, unless otherwise specified, "therapeutically effective amount" refers to the amount of a pharmaceutical active ingredient that will cause a biological or medical response in an individual for at least one of a disease, disorder and related symptoms, for example, the amount of a pharmaceutical active ingredient that brings at least one positive physiological and pharmacological effect to an individual, wherein at least one positive physiological and pharmacological effect includes but is not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression or preventing disease, etc.

[0337] The administration method of the preparations or compositions in the seventh aspect, eighth aspect, ninth aspect and tenth aspect of the present application can be oral administration independently, but is not limited thereto.

[0338] Some examples are provided below.

[0339] The embodiments of the present application will be described in detail below with reference to the examples. The following examples record the exemplary prescription composition, preparation method and quality standard results of the present application. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods for the unremarked conditions in the following examples are preferably referred to the guidance provided in the present application, and can also be based on the experimental manual or conventional conditions in this area, or according to the conditions recommended by the manufacturer, or with reference to experimental methods known in the art.

[0340] In the following examples, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument testing accuracy or operating accuracy are allowed.

[0341] In the following examples,

[0342] (1) Raw materials:

[0343] Nifedipine, a micronized product from Shaanxi Xiyue Pharmaceutical Co., Ltd.;

[0344] Povidone K90 and copovidone VA64, pharmaceutical-grade excipients from BASF;

[0345] Micronized silica gel, from Evonik Specialty Chemicals (Shanghai) Co., Ltd., pharmaceutical grade;

[0346] Sodium alginate and potassium alginate, from DuPont or Qingdao Mingyue Seaweed Group Co., Ltd., food or pharmaceutical grade;

[0347] Hydroxyethyl cellulose, Ashland (China) Investment Co., Ltd., pharmaceutical grade;

[0348] Sodium carboxymethyl starch, from Anhui Shanhe Excipients Co., Ltd., pharmaceutical grade;

[0349] Low-density hydroxypropyl cellulose, selected from Shin-Etsu Chemical Co., Ltd. of Japan, pharmaceutical grade;

[0350] Cellulose acetate, Eastman Company, pharmaceutical grade;

[0351] Hydroxypropyl methylcellulose, DuPont, USA;

[0352] Red iron oxide: Shanghai Yipin Pigment Co., Ltd., pharmaceutical grade;

[0353] Sodium chloride: Jiangsu Qinfen Pharmaceutical Co., Ltd.;

[0354] Magnesium stearate: Qufu Tianli Pharmaceutical Excipients Co., Ltd., pharmaceutical grade.

[0355] (2) Equipment:

[0356] Tablet hardness tester: Tianjin Tianda Tianfa Technology Co., Ltd., YD-20KZ;

[0357] Fluidized bed: Chuangzhi Electromechanical Technology Development Co., Ltd., FLZB-0.5;

[0358] Tablet press: Shandong Xinma Pharmaceutical Equipment Co., Ltd., SMA S60;

[0359] High-efficiency coating machine: Chuangzhi Electromechanical Technology Development Co., Ltd., CHC-38;

[0360] Laser drilling machine: Nanjing Ruichi Electronic Technology Engineering Co., Ltd., RC-YW-30;

[0361] High performance liquid chromatography: Agilent Technologies (China) Co., Ltd., Agilent 1260.

[0362] (3) Reagents:

[0363] Sodium dodecyl sulfate: Sinopharm Chemical Reagent Co., Ltd., analytical grade;

[0364] Sodium chloride: Sinopharm Chemical Reagent Co., Ltd., analytical grade;

[0365] Hydrochloric acid: Sinopharm Chemical Reagent Co., Ltd., analytical grade

[0366] Disodium hydrogen phosphate: Sinopharm Chemical Reagent Co., Ltd., analytical grade

[0367] Other ingredients such as citric acid and pancreatic enzyme were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0368] In the following examples, unless otherwise stated, the 1% sodium lauryl sulfate phosphate-citrate buffer medium used was prepared as follows: 7.15% disodium hydrogen phosphate-2.1% citric acid (77.3:22.7 volume ratio v / v), pH = 6.8, and this buffer was diluted 10 times with water before use.

[0369] 1. Preparation Example

[0370] 1.1. Formulation

[0371] (1) Prescription 1:

[0372] (2) Prescription 2:

[0373] (3) Prescription 3:

[0374] (4) Prescription 4:

[0375] (5) Prescription 5:

[0376] (6) Prescription 6:

[0377] (7) Prescription 7:

[0378] (8) Prescription 8:

[0379] (9) Prescription 9:

[0380] (10) Prescription 10:

[0381] (11) Prescription 11:

[0382] (12) Prescription 12:

[0383] (13) Prescription 13:

[0384] (14) Prescription 14:

[0385] (15) Comparative Prescription 1:

[0386] (16) Comparative Prescription 2:

[0387] (17) Comparative Prescription 3:

[0388] (18) Comparative Prescription 4:

[0389] (19) Comparative Prescription 5:

[0390] (20) Comparative Prescription 6:

[0391] (21) Comparative Prescription 7

[0392] (22) Comparative Prescription 8

[0393] 2. Preparation process

[0394] 2.1. Prescription Examples

[0395] In order to prepare the double-layer osmotic pump controlled-release tablets in each prescription example, the following preparation steps are included in order of the preparation process: (1) preparation of drug-containing composition particles; (2) preparation of push-layer particles; (3) compression of tablet cores; (4) coating with a controlled-release coating; (5) punching of coated tablets; and (6) coating with a water-soluble moisture-proof coating (if any).

[0396] (1) Preparation of drug-layered granules

[0397] Keep out of light. Evenly mix the prescribed amount of drug passed through a 60-mesh sieve with the excipients containing the drug layer, add to the fluidized bed, and spray with an 80% ethanol-water solution to granulate. Stop granulation when the appropriate particle size is reached. Dry, pass through a 20-mesh sieve to granulate, add magnesium stearate, mix thoroughly, and set aside.

[0398] (2) Preparation of booster layer particles

[0399] After the prescribed amount of booster layer excipients passed through a 60-mesh sieve is mixed evenly, the mixture is added to a fluidized bed and the aqueous solution is sprayed in for granulation. When the particle size reaches an appropriate size, the granulation is stopped and the mixture is dried. The granules are passed through a 20-mesh sieve and magnesium stearate is added. The mixture is mixed evenly and set aside.

[0400] (3) Tablet pressing

[0401] The drug-containing layer and booster layer granules prepared above were added to the hopper of a double-layer tablet press, and the double-layer tablet press was used to press into double-layer tablet cores of appropriate hardness. The hardness, content, and content uniformity of the double-layer tablet cores were measured.

[0402] (4) Packing isolation gown (if applicable)

[0403] According to the prescription composition of the example, an isolation coating aqueous solution was prepared; the above-mentioned qualified double-layer tablet cores were coated with the isolation coating coating solution, and the coated products were dried at 50°C for 12 hours to remove excess moisture.

[0404] (5) Controlled release coating

[0405] According to the prescription composition of the example, a controlled-release semipermeable membrane coating solution was prepared; the above-mentioned qualified double-layer tablet cores were coated with the controlled-release semipermeable membrane coating solution, and the coated products were dried at 50°C for 12 hours to remove excess organic solvent and moisture.

[0406] (6) Perforation of coated tablets

[0407] The coated tablets that have passed the inspection are punched with a laser puncher or mechanically to punch a drug-releasing hole with a diameter of 0.6 to 1.0 mm on the surface of the drug-containing layer of the tablets.

[0408] (7) Water-soluble film coating (if applicable)

[0409] Disperse the coating powder in water and dissolve it to prepare a coating solution with a solid content of 5-15%. Place the perforated tablets in a high-efficiency coating pan and coat them with the prepared coating solution until the desired coating weight gain is achieved. Dry at 60°C for 2 hours to remove excess water to obtain osmotic pump controlled-release tablets.

[0410] 2.2. Comparative Prescription Examples

[0411] According to the formula of the aforementioned comparative prescription example, the same method as that of preparing the prescription example osmotic pump controlled-release tablets was adopted.

[0412] 3. Experimental Examples

[0413] (1) Experimental Example 1: Determination of the Release Rates of Preparation Example Prescriptions 1 to 10 and Comparative Prescriptions 1 to 8 in 900 mL of Medium

[0414] Protect from light. Take this product and follow the apparatus for dissolution and release determination, method 2, in Appendix 0931 of Part IV of the Chinese Pharmacopoeia 2020. Place the tablet in a small metal mesh basket and use 900 mL of 1% sodium dodecyl sulfate phosphate-citrate buffer (prepared with 7.15% disodium hydrogen phosphate-2.1% citric acid (77.3:22.7 volume ratio v / v), pH = 6.8. Dilute this buffer 10-fold (volume ratio) with water before use) as the release medium. Set the speed to 100 rpm. Operate according to this method. Take 8 mL of the solution at 2, 4, 8, 12, 16, 20, and 24 hours, filter through a 0.45 μm microporous membrane, and use this as the test solution. Simultaneously, supplement with the same volume of release medium at the same temperature. Separately, accurately weigh approximately 18 mg of nifedipine reference substance and place it in a 50 mL brown volumetric flask. Dissolve it in 30 mL of methanol, dilute to the mark with water, and shake well. Accurately measure 5 mL and place it in a 50 mL brown volumetric flask. Dilute to the mark with 1% sodium lauryl sulfate in phosphate-citrate buffer and shake well to prepare this reference solution. Accurately measure 25 μL each of the reference solution and the test solution and inject them into a HPLC. Calculate the release amount per tablet at different times based on the peak area using the external standard method.

[0415] The HPLC detection chromatographic conditions are as follows: the chromatographic column is an octadecyl bonded silica gel column, the mobile phase is methanol:water (50:50), the flow rate is 1.0 mL / min, and the detection wavelength is 235 nm.

[0416] Table 1. Release of Preparation Example Prescriptions 1 to 10 in 900 mL of medium (n=6)

[0417] Table 2. Release of controlled-release tablets of preparation examples and comparison of prescriptions 1 to 8 in 900 mL of medium (n=3)

[0418] Table 3. Inter-tablet release differences of controlled-release tablets of Preparation Example 1 in 900 mL of medium (n=6)

[0419] Table 4. Differences in release between controlled-release tablets of Preparation Example 2 in 900 mL of medium (n=6)

[0420] As shown in Tables 1 and 2, the controlled-release tablets prepared according to the formulations of this application all exhibited 24-hour release rates exceeding 90%. In contrast, the controlled-release tablets of Comparative Formulations 1 and 3, which utilize hypromellose and / or copolyvidone as penetration-enhancing polymers, and Comparative Formulation 2, which utilize sodium alginate and carbomer as penetration-enhancing polymers, all exhibited 24-hour release rates less than 90%. However, the controlled-release tablets of Comparative Formulation 4, which utilizes the core tablets of the other party's formulations and is then coated with a release-controlling film, exhibited significantly improved release rates, reaching 94.1% within 24 hours.

[0421] In addition, compared to Prescription 8 (94.7% release in 24 hours), the 24-hour release of the controlled-release tablets of Comparative Prescriptions 5 and 8 was less than 90%. This shows that, under specific formulation compositions, the use of hydroxyethyl cellulose or sodium alginate alone, or the replacement of either hydroxyethyl cellulose or sodium alginate with a conventional polymer, may lead to a decrease in the final release rate. The combination of a hydroxyethyl cellulose and sodium alginate booster layer, in a structure without a barrier coat, facilitates the controlled release of the drug in the drug-containing layer and can significantly improve the final release rate of the tablet. The release curves of the tablets of the above formulations are shown in Figures 3 and 4.

[0422] The results in Tables 3 and 4 show that compared to Formulation 1, which uses a combination of hydroxyethyl cellulose and sodium alginate, Comparative Formulation 2, which uses carbomer as a permeation-enhancing polymer, exhibited significantly increased inter-tablet release variability. This is likely due to the carbomer in the push layer of Comparative Formulation 2 aggregating during the powder mixing or granulation process and failing to disperse evenly, resulting in poor push layer uniformity (Figure 5). Insufficient gel strength in some areas of the push layer led to uneven tablet release and significant inter-tablet variability. This indicates that the combination of hydroxyethyl cellulose and sodium alginate forms a high-strength, high-toughness hydrogel that helps improve the mechanical properties of the push layer composition, ensuring uniform release of the active ingredient from the drug-containing layer and increasing the ultimate drug release.

[0423] (2) Experimental Example 2: Preparation Example 11 to 14 Release Determination

[0424] ① Preparation Example Prescription 11 Release Study: Take the controlled-release tablets to be tested, and according to the second method of Appendix 0931 Dissolution and Release Determination of the Chinese Pharmacopoeia 2020 Edition, the tablets are placed in a small metal mesh basket, and 900 mL of artificial intestinal fluid without pancreatic enzymes is used as the solvent. The speed is 50 revolutions per minute. According to the operation, 8 mL of the solution is taken at 4 hours, 8 hours, 12 hours, 16 hours and 24 hours respectively, and filtered with a 0.45 μm microporous filter membrane. The filtrate is taken as the release test solution, and 8 mL of the above solvent is immediately added to the operating container.

[0425] Separately, take approximately 50 mg of glipizide reference substance, accurately weigh it, place it in a 100 mL volumetric flask, add 20 mL of methanol, sonicate to dissolve it, dilute it to the mark with methanol, shake well, and use it as the stock solution; take 1 mL of the stock solution, place it in a 100 mL volumetric flask, and dilute it to the mark with artificial intestinal fluid without pancreatic enzymes as the solvent to prepare the glipizide reference substance solution.

[0426] Take the control solution and the test solution respectively, measure the absorbance at a wavelength of 276nm by spectrophotometry, and calculate the release amount of each tablet at different times by the external standard method.

[0427] Release results: The release curve of the glipizide controlled-release tablets of Preparation Example 11 is shown in FIG6 .

[0428] ② Preparation Example Prescription 12 Release Study: Take the controlled-release tablets to be tested, and according to the second method of the dissolution and release determination method of the Chinese Pharmacopoeia 2020 Edition Part IV Appendix 0931, place the tablets in a small metal mesh basket, and use 500 mL of 0.1 M hydrochloric acid solution as the release medium. The speed is 50 revolutions per minute. Operate according to the law. After 4 hours, 8 hours, 12 hours, 16 hours and 24 hours, take 8 mL of the solution, centrifuge (8000 rpm, 15 min), take the supernatant as the test solution, and replenish the same volume of release medium in time. Separately, accurately weigh about 12.5 mg of the oxybutynin hydrochloride reference substance, place it in a 50 mL volumetric flask, dissolve it in acetonitrile, dilute it to the scale, and shake well. Accurately measure 1 mL of the solution, place it in a 25 mL volumetric flask, add 0.1 M hydrochloric acid solution to dilute to the scale, shake well, and use it as the reference solution; accurately measure 50 μL of the above reference solution and test solution respectively, inject them into the liquid chromatograph for measurement, and calculate the release amount of each tablet at different times by the peak area according to the external standard method.

[0429] The HPLC detection chromatographic conditions are as follows: the chromatographic column is an octadecylsilane bonded silica column; the mobile phase is acetonitrile-0.035M phosphate buffer (take 4.83 g of sodium dihydrogen phosphate, 5 mL of triethylamine, add water to 1000 mL, and adjust the pH value to 2.2±0.05 with phosphoric acid) (35:65 volume ratio); the detection wavelength is 220 nm; the flow rate is 1.5 mL / min; the injection volume is 10 μL.

[0430] Release results: The release curve of oxybutynin hydrochloride controlled-release tablets prepared in Example 12 is shown in FIG7 .

[0431] ③ Preparation Example Prescription 13 Release Study: Take the controlled-release tablets to be tested, and place the tablets in a small metal mesh basket according to the second method of Appendix 0931 Dissolution and Release Determination of the 2020 Edition of the Chinese Pharmacopoeia. Use 900 mL of 0.1 mol / L hydrochloric acid solution as the release medium, and rotate at 75 revolutions per minute. Operate according to the law. After 4 hours, 8 hours, 12 hours, 16 hours, and 24 hours, take 10 mL of the solution each time, centrifuge (8000 rpm, 15 min), take the supernatant as the release test solution, and at the same time add the same volume of release medium.

[0432] Separately, take about 10 mg of doxazosin mesylate reference substance, accurately weigh it, place it in a 50 mL volumetric flask, add 20 mL of methanol, ultrasonically treat it to dissolve it, dilute it to the scale with methanol, and shake it well; accurately measure 10 mL of the above solution, place it in a 100 mL volumetric flask, dilute it to the scale with 0.1 mol / L hydrochloric acid solution, shake it well, and use it as the stock solution; take 5 mL of the stock solution, place it in a 25 mL volumetric flask, and dilute it to the doxazosin mesylate reference substance solution with 0.1 mol / L hydrochloric acid solution as the solvent.

[0433] Take the test solution and the reference solution, and measure the absorbance at a wavelength of 245 nm according to the UV-visible spectrophotometry (Appendix IVA of Part II of the Chinese Pharmacopoeia 2005 edition), and calculate the release amount of each tablet at different times.

[0434] Release results: The release curve of the doxazosin mesylate controlled-release tablets prepared in Example 13 is shown in FIG8 .

[0435] ④ Preparation Example Prescription 14 Release Study: Take the controlled-release tablets to be tested, and according to the second method of the dissolution and release determination apparatus of Part IV of the Chinese Pharmacopoeia 2020, place the tablets in a small metal mesh basket, and use 500 mL of 0.2% (w / v) sodium chloride hydrochloric acid solution (hydrochloric acid concentration is about 0.1 mol / L) as the release medium. The speed is 50 revolutions per minute. Operate according to the law. After 2 hours, 4 hours, 8 hours, 12 hours, 14 hours and 24 hours, take 8 mL of the solution each time, centrifuge (8000 rpm, 15 min), and take the supernatant as the test solution; at the same time, add the same volume of release medium. Separately, take an appropriate amount of paliperidone reference substance, accurately weigh it, dissolve it in methanol and dilute it to make a solution containing 60 μg of paliperidone per 1 mL, which is used as the reference substance stock solution; accurately measure an appropriate amount of the reference substance stock solution, add 0.2% sodium chloride (w / v, %) hydrochloric acid solution to make a solution containing 12 μg of paliperidone per 1 mL, which is used as the reference substance solution.

[0436] Accurately measure 20 μL of the reference solution and the test solution, inject them into the liquid chromatograph, record the chromatogram, and calculate the release amount of each tablet at different times based on the peak area according to the external standard method.

[0437] The HPLC detection conditions are as follows: the chromatographic column is filled with octadecylsilane bonded silica gel; the mobile phase is methanol-ammonium formate buffer (pH 3.3±0.1) (take 4.2 g of ammonium formate, add an appropriate amount of water to dissolve, add 5 mL of formic acid, and dilute with water to 4000 mL) = 35:65; the detection wavelength is 275 nm; the flow rate is 1.0 mL per minute, and the injection volume is 20 μL.

[0438] Release results: The release curve of paliperidone controlled-release tablets prepared in Example 14 is shown in FIG9 .

[0439] It can be seen that the use of the push layer composition described in the present application helps to improve the mechanical properties of the push layer composition, and can form a high-strength and high-toughness hydrogel in an aqueous medium; the push layer composition provided in the present application can be used for the controlled-release administration of various active ingredients (including glipizide, oxybutynin hydrochloride, doxazosin mesylate, paliperidone, etc.), and can achieve complete release of the active ingredients in different dissolution media.

[0440] (3) Experimental Example 3: Release Determination of Preparation Example Prescription 1 and Comparative Prescription 2 in 100 mL of Medium

[0441] Protect from light. Take the controlled-release tablets and place them in a small metal mesh basket. Add 100 mL of 1% sodium dodecyl sulfate phosphate-citrate buffer (prepared as 7.15% disodium hydrogen phosphate-2.1% citric acid (77.3:22.7 volume ratio v / v), pH = 6.8, and dilute this buffer 10-fold by volume with water before use) as the release medium. The rotation speed is 50 rpm. Operate according to the above method. Take 8 mL of the solution at 4 hours, 8 hours, 12 hours, 16 hours, and 24 hours respectively. Filter through a 0.45 μm microporous membrane. At the same time, replenish the same volume of release medium at the same temperature. Take the above filtrate and dilute it 10-fold by volume to prepare the test solution.

[0442] Separately, take approximately 18 mg of nifedipine reference substance, accurately weigh it, place it in a 50 mL brown volumetric flask, add 30 mL of methanol to dissolve it, dilute it to the mark with water, and shake well; accurately measure 5 mL, place it in a 50 mL brown volumetric flask, dilute it to the mark with 1% sodium lauryl sulfate phosphate-citrate buffer, and shake well to prepare the reference substance solution.

[0443] Accurately measure 25 μL of the reference solution and the test solution, inject them into the high performance liquid chromatography, use an octadecyl bonded silica gel column, the mobile phase is methanol: water = 50:50, the flow rate is 1.0 mL / min, the detection wavelength is 235 nm, and the peak area is used to calculate the cumulative release of each tablet at different times according to the external standard method.

[0444] Table 5. Release of nifedipine controlled-release tablets from preparation example 1 in 100 mL of medium (n=6)

[0445] Table 6. Release of nifedipine controlled-release tablets in 100 mL of medium (n=6) according to the preparation example and the comparative formulation 2

[0446] As can be seen from the results in Tables 5, 6 and Figure 10, when the release rate was measured at a lower medium volume (100 mL), the inter-tablet release difference of the nifedipine controlled-release tablets of Comparative Prescription 2 was greater than that of Prescription 1. Comparative Prescription 2 used a conventional combination of sodium alginate, carbomer and copovidone VA64. In the absence of an isolation coat, there was an incomplete release phenomenon (<90%). It is speculated that its absorption was relatively poorer in the lower part of the intestine (the intestinal segment with relatively low water content).

[0447] (4) Experimental Example 4: Release Study of Preparation Example Prescription 2 and Comparative Prescription 2 in Ethanol Solutions of Different Concentrations

[0448] Protect from light. Place the controlled-release tablets to be tested in a small metal mesh basket. Add 5%, 10%, 20%, or 40% (v / v) anhydrous ethanol to the prepared buffer containing 1% sodium lauryl sulfate. Mix thoroughly. Pour 900 mL of each 5%, 10%, 20%, or 40% ethanol solution into the test release medium at 100 rpm. Continue this procedure. After 2, 4, 8, and 12 hours, remove 8 mL of each solution and filter through a 0.45 μm microporous filter membrane to prepare the test solution. Simultaneously, add the same volume of release medium at the same temperature. Separately, accurately weigh approximately 18 mg of nifedipine reference substance and place it in a 50 mL brown volumetric flask. Dissolve it in 30 mL of methanol, dilute to the mark with water, and shake well. Accurately measure 5 mL and place it in a 50 mL brown volumetric flask. Dilute to the mark with release medium and shake well to prepare the reference solution. Accurately measure 25 μL of the reference solution and the test solution, inject them into high performance liquid chromatography, use an octadecyl bonded silica gel column, the mobile phase is methanol: water = 50:50, the flow rate is 1.0 mL / min, and the detection wavelength is 235 nm.

[0449] The results are shown in Figures 11 and 12. Different concentrations of ethanol affect the release rate of the controlled-release tablets of this application, with a trend toward accelerated release in the first two hours. The release trends of Formulation 2 and Comparative Formulation 2 in release media with different ethanol concentrations were essentially the same, similar to the release profile at pH 6.8. However, the release differences between Comparative Formulation 2 tablets in different ethanol concentrations were greater.

[0450] (5) Experimental Example 5: Release Study of Preparation Example Formula 2 and Comparative Formula 3 in pH 6.8 Artificial Intestinal Fluid

[0451] With reference to Appendix 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, a simulated artificial intestinal fluid with a pH of 6.8 was prepared. The preparation method was as follows: 6.8 g of potassium dihydrogen phosphate was taken, 500 mL of water was added to dissolve it, the pH value was adjusted to 6.8 with 0.1 mol / L sodium hydroxide solution, 10 g of Tween 80 was added to disperse and dissolve it; another 10 g of pancreatic enzyme was taken, an appropriate amount of water was added to dissolve it, the two solutions were mixed, and the mixture was diluted to 1000 mL with water.

[0452] Protect from light. Take the controlled-release tablet to be tested and use 900 mL of the simulated intestinal fluid as the release medium at 100 rpm. Follow the same procedure as described above. At 4, 8, 12, 16, and 24 hours, take 8 mL of the solution each time. Filter through a 0.45 μm microporous filter membrane and replenish the same volume of release medium at the same temperature. Centrifuge at 8000 rpm for 10 minutes, and discard the supernatant to prepare the test solution. Separately, accurately weigh approximately 30 mg of nifedipine reference substance and place it in a 100 mL brown volumetric flask. Dissolve it in 50 mL of methanol, dilute to the mark with water, and shake well. Accurately measure 5 mL and place it in a 50 mL brown volumetric flask. Dilute to the mark with release medium and shake well to prepare the reference solution. Accurately measure 25 μL of the reference solution and the test solution, inject them into high performance liquid chromatography, use octadecyl bonded silica gel column, the mobile phase is methanol: water (50:50), the flow rate is 1.0 mL / min, the detection wavelength is 235 nm, and the peak area is used to calculate the cumulative release of each tablet at different time points according to the external standard method.

[0453] The results show ( FIG13 ) that, compared with the formulation 2 of the preparation example, the 24-hour release of the comparative formulation 3 is lower and cannot be fully released. The controlled-release tablet (formulation 2) of the present application has a more stable drug release in simulated intestinal fluid.

[0454] (6) Experimental Example 6: Pharmacokinetic Study of Preparation Example Prescription 6 and Comparative Prescription 3 in Dogs

[0455] Twelve healthy Beagle dogs weighing 10.3-12.5 kg were provided by Beijing Mas Biotechnology Co., Ltd. and housed under a 12-hour light-dark cycle, at a temperature of 22±1°C and a humidity of 60±5%. The dogs were fasted for 12 hours (with free access to water) and given one controlled-release nifedipine tablet, either Formulation 6 or Control Formulation 3. Blood was drawn at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, and 48 hours. Blood samples were centrifuged at 4000 rpm, and plasma was stored at -80°C. Liquid chromatography / mass spectrometry (LC-MS) was used to analyze plasma drug concentrations, and pharmacokinetic curves were constructed and statistically analyzed for pharmacokinetic parameters. During the experiment, the controlled-release tablet shells excreted by the Beagle dogs were collected, and the residual drug content in the tablet core was determined.

[0456] Take the coated tablet excreted above and cut it into four pieces with a razor blade to fully expose the tablet core contents. Place it in a 100mL brown volumetric flask and add methanol-water (50:50 by volume) to fully dissolve it. Dose to volume, shake well, and filter through a 0.45μm microporous filter to prepare the test solution. Separately, accurately weigh 18mg of nifedipine reference substance and place it in a 100mL brown volumetric flask. Dissolve it in 50mL of methanol. Dilute to the mark with water and shake well to prepare the reference solution. Accurately measure 25μL each of the reference solution and the test solution and inject them into a high-performance liquid chromatography (HPLC) column using an octadecyl bonded silica gel column with a mobile phase of methanol:water (50:50 by volume) at a flow rate of 1.0mL / min and a detection wavelength of 235nm.

[0457] Table 7. Results of blood drug concentration determination after oral administration of nifedipine controlled-release tablets of Preparation Example 6 to dogs

[0458] Table 8. Results of blood drug concentration determination after oral administration of nifedipine controlled-release tablets in dogs compared with those in Prescription 3 in Preparation Example

[0459] Table 9. Pharmacokinetic results in Beagle dogs

[0460] The results of the canine pharmacokinetic study of Preparation Example Prescription 6 and Comparative Prescription 3 are shown in Tables 7, 8, 9, and Figure 14. The nifedipine controlled-release tablets of Prescription 6 exhibited less individual variability in in vivo absorption in dogs than the tablets of Comparative Prescription 3. The use of the booster layer composition of the present application helps improve the mechanical properties of the booster layer composition. In an aqueous medium, the booster layer polymer can form a high-strength, high-toughness hydrogel, which facilitates more stable release between tablets, reduces residual drug in the tablet core, and provides more complete drug release and improved in vivo release uniformity.

[0461] Compared with the nifedipine controlled-release tablets of prescription 3, the C max The AUC is higher, which may be because the booster layer composition of the present application can achieve more uniform and complete release, which is conducive to complete absorption of the drug in the body.

[0462] (7) Experimental Example 7: Quality Assessment of Tablet Cores of Preparation Example Prescriptions 4, 5, 8, Comparative Prescriptions 2, and 5

[0463] The push layer penetration enhancers, water-insoluble polymers and osmotic pressure enhancers, such as sodium alginate, sodium carboxymethyl cellulose, sodium chloride and other excipients, have low adhesion and the compressed tablet cores have poor brittleness. In the subsequent coating process, the push layer is easily broken and lost due to collisions between tablets during the rolling coating process, resulting in coating failure or release differences between tablets.

[0464] In this study, double-layer tablet cores compressed from the drug-containing layer and booster layer particles of the above different embodiments were placed in a coating pan (Chuangzhi CHC-38). The coating parameters were adjusted (main machine speed 20 rpm, air inlet temperature 30°C, spray pressure 0.05 MPa). Samples were taken after rolling for 5 minutes, 10 minutes, and 30 minutes, weighed, and the friability was calculated (calculation formula: loss weight / original weight × 100%).

[0465] The results can be found in Table 10 and Figure 15. The appearance of the tablets after 30 minutes of tumbling can be found in Figure 15. The formulation without hydroxyethyl cellulose (Comparative Formulation 5) exhibited significantly greater friability after tumbling in the coating pan, reaching nearly 4.3% after 30 minutes of tumbling. Comparative Formulation 2, using copovidone VA64 as the binder, showed relatively improved friability after tumbling in the coating pan, but still remained near 1.2% after 30 minutes of tumbling.

[0466] The tablet cores of Prescription 4, Prescription 5 and Prescription 8 using hydroxyethyl cellulose had good friability after rolling in the coating pan as the amount of hydroxyethyl cellulose increased. The friability after rolling for 30 minutes was 0.4%, 0.2% and 0.1% respectively.

[0467] It can be seen that in terms of preparation technology, the addition of hydroxyethyl cellulose can also help improve the friability of the tablet cores compressed by the drug-containing layer and the push layer, increase the quality stability of the double-layer tablet cores, reduce the quality differences of the tablet cores caused by the friability differences between tablets in the push layer during the coating process, and improve the defect of large release differences within product batches.

[0468] Table 10. Coating friability of different formulations in the coating pan

[0469] The technical features of the above-mentioned embodiments and examples can be combined in any appropriate manner. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0470] The above embodiments only express several implementation methods of the present application, which are convenient for understanding the technical solutions of the present application in detail, but cannot be understood as limiting the scope of protection of the present application. It should be pointed out that, for ordinary technicians in this field, without departing from the concept of the present application, several variations and improvements can be made, which all fall within the scope of protection of the present application. In addition, it should be understood that after reading the above teaching content of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the scope of protection of the present application. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent of this application shall be based on the content of the attached claims, and the description and drawings can be used to explain the content of the claims.

Claims

1. An osmotic pump controlled-release preparation comprising the following structures arranged in order from inside to outside: A tablet core comprising a drug-containing layer and a booster layer; a controlled-release coating layer with drug-releasing holes; and Optional water-soluble film coating; in, The drug-releasing hole communicates with the drug-containing layer and the exterior of the osmotic pump controlled-release preparation; the booster layer is located on a side of the drug-containing layer away from the drug-releasing hole; Wherein, the drug-containing layer is composed of a pharmaceutical active ingredient, a hydrophilic polymer carrier and a pharmaceutical excipient F1; wherein, the pharmaceutical excipient F1 is a pharmaceutical excipient different from the hydrophilic polymer carrier; The boost layer is composed of a penetration-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure enhancer and a pharmaceutical excipient F2; wherein the penetration-promoting polymer contains hydroxyethyl cellulose and alginate; the water-insoluble swelling polymer includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone; wherein the pharmaceutical excipient F2 is a pharmaceutical excipient different from the penetration-promoting polymer, the water-insoluble swelling polymer and the osmotic pressure enhancer.

2. The osmotic pump controlled-release preparation according to claim 1, wherein The penetration-promoting polymer comprises hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer is any one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, or a combination thereof; or The penetration-promoting polymer is hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer includes at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone; or, The penetration-promoting polymer is hydroxyethyl cellulose and alginate, and the water-insoluble swelling polymer is any one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, or a combination thereof.

3. The osmotic pump controlled-release preparation according to claim 1 or 2, which satisfies one or more of the following characteristics: Based on the total weight of the drug-containing layer, the active pharmaceutical ingredient accounts for 4% to 33% of the weight of the drug-containing layer, the hydrophilic polymer carrier accounts for 40% to 96% (optionally 40% to 95%, alternatively 40% to 94%, alternatively 65% ​​to 96%, alternatively 65% ​​to 94%, alternatively 65% ​​to 85%) of the weight of the drug-containing layer, and the pharmaceutical excipient F1 accounts for 0 to 2% of the weight of the drug-containing layer; Based on the total weight of the push layer, the penetration-promoting polymer accounts for 11% to 66% of the weight of the push layer (optionally 12% to 65%, alternatively 20% to 65%, alternatively 11% to 50%, alternatively 20% to 50%, and alternatively 20% to 40%), the water-insoluble swellable polymer accounts for 12% to 71% of the weight of the push layer (optionally 13% to 70%, further optionally 15% to 60%, further optionally 20% to 50%, and further optionally 20% to 40%), the osmotic pressure enhancer accounts for 10% to 45% of the weight of the push layer (optionally 14% to 42%, further optionally 15% to 40%), and the pharmaceutical excipient F2 accounts for 0.5% to 2.5% of the weight of the push layer; The weight ratio of the drug-containing layer to the booster layer is 0.5-2, optionally 0.8-1.6, further optionally 0.8-1.5, further optionally 0.9-1.5; The controlled-release coating layer with drug-releasing holes has a weight gain of 6% to 25% of the weight of the tablet core, optionally 6% to 21%, further optionally 8% to 25%, further optionally 8% to 15%, further optionally 10% to 20%.

4. The osmotic pump controlled-release preparation according to any one of claims 1 to 3, wherein Based on the total weight of the drug-containing layer, the active pharmaceutical ingredient accounts for 4% to 33% of the weight of the drug-containing layer, the hydrophilic polymer carrier accounts for 40% to 96% (optionally 40% to 95%, alternatively 40% to 94%, alternatively 65% ​​to 96%, alternatively 65% ​​to 94%, alternatively 65% ​​to 85%) of the weight of the drug-containing layer, and the pharmaceutical excipient F1 accounts for 0 to 2% of the weight of the drug-containing layer; Based on the total weight of the push layer, the penetration-promoting polymer accounts for 11% to 66% of the weight of the push layer (optionally 12% to 65%, alternatively 20% to 65%, alternatively 11% to 50%, alternatively 20% to 50%, and alternatively 20% to 40%), the water-insoluble swellable polymer accounts for 12% to 71% of the weight of the push layer (optionally 13% to 70%, further optionally 15% to 60%, further optionally 20% to 50%, and further optionally 20% to 40%), the osmotic pressure enhancer accounts for 10% to 45% of the weight of the push layer (optionally 14% to 42%, further optionally 15% to 40%), and the pharmaceutical excipient F2 accounts for 0.5% to 2.5% of the weight of the push layer; The weight ratio of the drug-containing layer to the booster layer is 0.5-2, optionally 0.8-1.6, further optionally 0.8-1.5, further optionally 0.9-1.5; The weight gain of the controlled-release coating layer with drug-releasing holes is 6% to 25% of the weight of the tablet core, optionally 6% to 21%, further optionally 8% to 25%, further optionally 8% to 15%, further optionally 10% to 20%.

5. The osmotic pump controlled-release preparation according to any one of claims 1 to 4, wherein There is no isolation coating between the core tablet and the controlled release coating layer.

6. The osmotic pump controlled-release preparation according to any one of claims 1 to 5, which satisfies one or more of the following characteristics: The boost layer does not contain polyethylene oxide; The boost layer does not contain carbomer; The alginate in the penetration-promoting polymer is selected from one or more of sodium alginate, potassium alginate and ammonium alginate.

7. The osmotic pump controlled-release preparation according to any one of claims 1 to 6, which satisfies one or more of the following characteristics: There are one or more drug release holes, and any one of the drug release holes communicates with the drug-containing layer and the outside of the osmotic pump controlled-release preparation; The diameter of the drug-releasing hole is 0.6-1.0 mm.

8. The osmotic pump controlled-release preparation according to any one of claims 1 to 7, wherein The drug-containing layer satisfies one or more of the following characteristics: The hydrophilic polymer carrier is povidone, copovidone or a combination thereof; The pharmaceutical excipient F1 is selected from one or more of an anti-osmotic agent, an antistatic agent and a lubricant.

9. The osmotic pump controlled-release preparation according to claim 8, wherein The drug-containing layer satisfies one or more of the following characteristics: The penetration enhancer is selected from one or more of sodium chloride, potassium chloride, sorbitol, xylitol, glucose and sucrose, and may be sodium chloride; The antistatic agent includes one or more of micropowder silica gel, stearic acid and polyethylene glycol, and micropowder silica gel can be selected; the lubricant is selected from one or more of magnesium stearate, polyethylene glycol, sodium stearyl fumarate and talc.

10. The osmotic pump controlled-release preparation according to any one of claims 1 to 9, wherein In the push-boost layer, the penetration-promoting polymer mainly comprises hydroxyethyl cellulose and alginate; Optionally, the sum of the weights of the hydroxyethyl cellulose and the alginate accounts for more than 80% by weight of the penetration-enhancing polymer.

11. The osmotic pump controlled-release preparation according to claim 10, wherein The boost layer satisfies one or more of the following characteristics: In the boosting layer, the weight ratio of the hydroxyethyl cellulose to the alginate is 1:(1-60), optionally 1:(1.5-40), further optionally 1:(1.5-25), further optionally 1:(1.5-20), further optionally 1:(1.5-16); The weight proportion of the hydroxyethyl cellulose in the boosting layer is 0.4% to 22% (optionally 0.5% to 20%).

12. The osmotic pump controlled-release preparation according to any one of claims 1 to 11, wherein In the push layer, the pharmaceutical excipient F2 is selected from one or more of a lubricant, a colorant and a glidant.

13. The osmotic pump controlled-release preparation according to any one of claims 1 to 12, wherein In the push-assist layer, the water-insoluble swellable polymer includes at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, and optionally includes one or more of cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone.

14. The osmotic pump controlled-release preparation according to any one of claims 1 to 13, wherein In the boosting layer, the osmotic pressure enhancer is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, sorbitol, xylitol, glucose and sucrose, and sodium chloride can be selected.

15. The osmotic pump controlled-release preparation according to any one of claims 1 to 14, wherein The controlled-release coating layer with drug-releasing pores is composed of a semipermeable controlled-release coating membrane material and an optional pharmaceutical excipient F3; wherein the pharmaceutical excipient F3 is one or more of a plasticizer and a pore-forming agent.

16. The osmotic pump controlled-release preparation according to claim 15, which satisfies one or more of the following characteristics: The semipermeable controlled-release coating material is cellulose acetate or a premixed coating powder containing cellulose acetate; The pharmaceutical excipient F3 is selected from one or more of polyethylene glycol, diethyl phthalate, triethyl citrate, triacetin and dibutyl sebacate; The weight ratio of the pharmaceutical excipient F3 to the sum of the weight of the semipermeable controlled-release coating material and the pharmaceutical excipient F3 is 0-20%, optionally 1%-10%, and further optionally 1%-7.4%.

17. The osmotic pump controlled-release preparation according to any one of claims 1 to 16, wherein The weight gain of the water-soluble coating film is 5% to 20% of the total weight of the tablet core and the controlled-release coating layer with drug-releasing holes.

18. The osmotic pump controlled-release preparation according to any one of claims 1 to 17, wherein The active pharmaceutical ingredient is selected from any one of nifedipine, glipizide, oxybutynin hydrochloride, doxazosin mesylate and paliperidone.

19. The osmotic pump controlled-release preparation according to claim 18, wherein The active ingredient of the medicine is nifedipine.

20. The osmotic pump controlled-release preparation according to any one of claims 1 to 19, wherein The drug-containing layer and the boosting layer constitute a double-layer tablet core.

21. The osmotic pump controlled-release preparation according to any one of claims 1 to 20, wherein The osmotic pump controlled-release preparation is controlled to release at 37° C. and 100 rpm. The release behavior of the active pharmaceutical ingredient in the osmotic pump controlled-release preparation satisfies one or more of the following release properties: The release rate at 4 hours was greater than 4%; The release at 12 hours is greater than 40%; and The release rate at 24 hours is greater than 90%; Alternatively, the release medium is 900 mL of 1% sodium lauryl sulfate phosphate-citrate buffer, 900 mL of Artificial intestinal fluid of pancreatic enzyme, 500 mL of 0.1 mol / L hydrochloric acid solution, 900 mL of 0.1 mol / L hydrochloric acid solution or 500 mL of 0.2% (w / v) sodium chloride in 0.1 mol / L hydrochloric acid solution.

22. An osmotic pump controlled-release composition, comprising the components of the osmotic pump controlled-release preparation according to any one of claims 1 to 21, for preparing the osmotic pump controlled-release preparation.

23. A method for preparing the osmotic pump controlled-release preparation according to any one of claims 1 to 21, comprising the following steps in sequence: Prepare drug-containing layer granules according to the components of the drug-containing layer, and prepare booster layer granules according to the components of the booster layer; Pressing the drug-containing layer particles and the push layer particles into the tablet core in a mold; Coating the outer surface of the core tablet with a controlled-release coating layer, and then punching holes in the controlled-release coating layer to form the controlled-release coating layer with drug-releasing holes; Optionally, the water-soluble coating film is coated.

24. A push layer composition, comprising a permeation-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure enhancer, and a pharmaceutical excipient F2; wherein: The definitions of the penetration-promoting polymer, the water-insoluble swelling polymer, the osmotic pressure enhancer and the pharmaceutical excipient F2 are as defined in any one of claims 1 to 21; Optionally, the penetration-promoting polymer is a combination of hydroxyethyl cellulose and alginate.

25. Use of the osmotic pump controlled-release preparation according to any one of claims 1 to 21 as an oral controlled-release preparation.

26. Use of the osmotic pump controlled-release preparation according to any one of claims 1 to 21, or the osmotic pump controlled-release composition according to claim 22, or the booster layer composition according to claim 24 in the preparation of a medicament for at least one of preventing and treating cardiovascular diseases, wherein: The active ingredient of the medicine is nifedipine, and the cardiovascular disease includes at least one of hypertension and chronic stable angina pectoris of coronary heart disease.

27. A method for preventing cardiovascular disease, comprising administering to a subject a preventively effective amount of the osmotic pump controlled-release preparation according to any one of claims 1 to 21, or administering to a subject a preventively effective amount of the osmotic pump controlled-release composition according to claim 22; Optionally, the cardiovascular disease includes at least one of hypertension and chronic stable angina pectoris of coronary heart disease.

28. A method for treating cardiovascular disease, comprising administering to a subject a therapeutically effective amount of the osmotic pump controlled-release preparation according to any one of claims 1 to 21, or administering to a subject a therapeutically effective amount of the osmotic pump controlled-release composition according to claim 22; Optionally, the cardiovascular disease includes at least one of hypertension and chronic stable angina pectoris of coronary heart disease.

29. An osmotic pump controlled-release preparation for at least one of preventing and treating cardiovascular diseases, the osmotic pump controlled-release preparation being as defined in any one of claims 1 to 21; Optionally, the cardiovascular disease includes at least one of hypertension and chronic stable angina pectoris of coronary heart disease.

30. An osmotic pump controlled-release composition for use in at least one of preventing and treating cardiovascular diseases, wherein the osmotic pump controlled-release composition is as defined in claim 22.

Images