WO2024022382A1 - 渗透泵控释制剂、渗透泵控释组合物、制备方法和应用 - Google Patents

渗透泵控释制剂、渗透泵控释组合物、制备方法和应用 Download PDF

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WO2024022382A1
WO2024022382A1 PCT/CN2023/109305 CN2023109305W WO2024022382A1 WO 2024022382 A1 WO2024022382 A1 WO 2024022382A1 CN 2023109305 W CN2023109305 W CN 2023109305W WO 2024022382 A1 WO2024022382 A1 WO 2024022382A1
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Prior art keywords
release
layer
drug
osmotic pump
optionally
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PCT/CN2023/109305
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English (en)
French (fr)
Inventor
甘勇
朱春柳
朱全垒
王素云
尤恒
胡杰
颜虎
Original Assignee
中国科学院上海药物研究所
青岛黄海制药有限责任公司
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Publication of WO2024022382A1 publication Critical patent/WO2024022382A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • 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 application.
  • osmotic pump preparations were first developed by the American company ALZA in 1970, and more than ten products have been on the market since 1983. At present, osmotic pump preparations are mainly used for drugs with short half-lives or requiring frequent administration and narrow therapeutic windows, such as drugs for the treatment of cardiovascular diseases, angina, hypertension, asthma and other chronic diseases.
  • the traditional push-pull osmotic pump with a double-layer tablet core is a semi-permeable membrane-coated tablet with a drug release hole.
  • the tablet core is composed of a drug-containing layer and a booster layer.
  • the drug-containing layer in the tablet core is composed of drug, It is composed of a hydrophilic polymer carrier and other excipients, and the booster layer in the tablet core is composed of one or more sustained-release polymers, osmotic pressure enhancers and other excipients.
  • the tablet core is covered with a semipermeable membrane, and drug release holes are provided on both sides of the semipermeable membrane. The drug is connected to the external environment through the drug release holes.
  • One of the drug release principles of the double-layer push-pull osmotic pump is the "controlled" expansion of the polymer in the booster layer when it encounters water. Under this expansion, the drug-containing layer is pushed out of the film pores. , thereby achieving drug release. Therefore, the polymer in the booster layer needs to have both a swelling boosting effect and an appropriate swelling control effect to achieve controlled release of the drug. Therefore, the type and amount of polymer excipients in the booster layer are key factors in controlling drug release in double-layer osmotic pump controlled-release tablets.
  • the polymer in the booster layer of double-layer osmotic pump controlled-release tablets mainly uses two types of functional excipients.
  • One type is a permeation-promoting polymer that can control the swelling rate of the booster layer.
  • This type of polymer is generally a water-soluble polymer that can gel after absorbing water and swelling.
  • the high-viscosity gel can adjust the overall expansion rate of the booster layer.
  • known penetration-enhancing polymers include high molecular weight polyoxyethylene, carbomer, hydroxypropylmethylcellulose, povidone, copovidone, hydroxypropylcellulose, etc.
  • Another type of functional excipient in the booster layer is an insoluble polymer that can expand rapidly when exposed to water.
  • insoluble polymer swells quickly when exposed to water and can be used as a drug release force for the booster layer.
  • Known water-insoluble polymers Including carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, etc.
  • Penetration-promoting polymers are a type of polymers that have strong water-absorbing swelling properties. Some polymers can achieve multiple functions of controlled release through a single polymer component.
  • the push-pull osmotic pump products Adalat GITS (Baixintong), Glucotrol achieving zero-order release of drugs.
  • the double-layer controlled-release tablets of flurbiprofen described in patent document CN103816131A and the double-layered controlled-release tablets of posaconazole described in patent document CN103948558A also use polyoxyethylene as the penetration-promoting polymer in the booster layer.
  • Patent document CN101856337A describes an osmotic controlled-release drug delivery system using sodium alginate as a penetration-promoting polymer, in which sodium alginate is used as a penetration-promoting polymer and combined with other polymers such as copovidone and sodium carboxymethyl starch.
  • this preparation requires a layer of isolation coat between the inner surface of the controlled-release coating and the tablet core to reduce the shear force between the tablet core and the controlled-release coating to achieve relatively good drug release. Without an isolation gown, the release rate at 24 hours is only 83.4%.
  • the push-pull double-layer controlled release tablets described in patent documents CN100563638C and CN100563637C use any one of carbomer, hypromellose, copovidone or a combination thereof as the main penetration-promoting polymer of the booster layer.
  • the nifedipine controlled-release preparation described in patent document CN100563637C uses carbomer as a penetration-promoting polymer.
  • carbomer due to the strong static electricity of oral pharmaceutical grade carbomer powder, it is easy to agglomerate itself, which can easily lead to poor uniformity in the powder mixing and granulation process. It is difficult to control the uniformity of tablets, and even leads to inconsistent release in some production batches. Stable or incomplete release (release at 24 hours ⁇ 90%).
  • Other formulations that do not contain carbomer, such as those using hypromellose, copovidone, or a combination of the two as penetration-promoting polymers have insufficient boosting force, resulting in incomplete drug release (24 hourly release ⁇ 90%).
  • the osmotic pump controlled-release preparation has a simple formula and can control the stable release of drugs in 16 to 24 hours without being coated with an isolation film.
  • the release rate in 24 hours can be greater than 90%.
  • osmotic pump controlled release compositions for preparing the osmotic pump controlled release preparations, preparation methods and applications are also provided.
  • an osmotic pump controlled-release preparation which includes the following structures arranged in sequence from the inside to the outside:
  • a tablet core composed of a drug-containing layer and a booster layer
  • a controlled release coating layer with drug release holes A controlled release coating layer with drug release holes
  • Optional water-soluble coating film (the water-soluble coating film can be used as at least one of a moisture-proof film and an aesthetic coat).
  • the drug release hole communicates with the outside of the drug-containing layer and the osmotic pump controlled release preparation; the booster layer is located on the side of the drug-containing layer away from the drug release hole;
  • the drug-containing layer is composed of pharmaceutical active ingredients, hydrophilic polymer carrier and pharmaceutical excipient F1; wherein, the pharmaceutical excipient F1 is a pharmaceutical excipient different from the hydrophilic polymer carrier;
  • the boosting layer is composed of a penetration-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure accelerator and pharmaceutical excipients F2; wherein the penetration-promoting polymer contains hydroxyethyl cellulose and alginate; the water
  • the insoluble swelling polymer includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; wherein, the pharmaceutical excipient F2 is Pharmaceutical excipients that are different from the penetration-promoting polymer, the water-insoluble swelling polymer and the osmotic pressure enhancer.
  • the penetration-promoting polymer includes hydroxyethyl cellulose and sodium alginate
  • the water-insoluble swelling polymer is carboxymethyl starch salt, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl starch Any one or combination of cellulose sodium and crospovidone; or,
  • the penetration-promoting polymer is hydroxyethyl cellulose and sodium alginate
  • the water-insoluble swelling polymer includes carboxymethyl starch salt, low-substituted hydroxypropyl cellulose, croscarmellose sodium and cross-linked at least one of povidone; or,
  • the penetration-promoting polymer is hydroxyethyl cellulose and sodium alginate
  • the water-insoluble swelling polymer is carboxymethyl starch salt, low-substituted hydroxypropyl cellulose, croscarmellose sodium and cross-linked Any one or combination of povidones.
  • the osmotic pump controlled release formulation meets one or more of the following characteristics:
  • 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 (can be Choose 40% ⁇ 95%, another choice is 40% ⁇ 94%, another choice is 65% ⁇ 96%, another choice is 65% ⁇ 94%, another choice is 65% ⁇ 85%), so
  • the pharmaceutical excipient F1 accounts for 0 to 2% of the weight of the drug-containing layer;
  • the penetration-promoting polymer accounts for 11% to 66% of the weight of the boosting layer (optional 12% to 65%, optionally 20% to 65%, optionally
  • the water-insoluble swelling polymer accounts for 12% to 71% of the weight of the booster layer.
  • the osmotic pressure accelerator accounts for 10% to 45% of the weight of the boosting layer (optional 14% to 42%, further optional 15% to 40%)
  • the medicinal excipient F2 accounts for 0.5% to 0.5% of the weight of the boosting layer. 2.5%;
  • the weight ratio of the drug-containing layer and the boosting layer is 0.5 ⁇ 2, optionally 0.8 ⁇ 1.6, optionally 0.8 ⁇ 1.5, optionally 0.9 ⁇ 1.5;
  • 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%, optionally 8% to 25%, optionally 8% % ⁇ 15%, optional 10% ⁇ 20%.
  • the pharmaceutical active ingredient accounts for 4% to 33% of the weight of the drug-containing layer
  • the hydrophilic polymer carrier accounts for 40% of the weight of the drug-containing layer.
  • % ⁇ 96% (optional 40% ⁇ 95%, optional 40% ⁇ 94%, optional 65% ⁇ 96%, optional 65% ⁇ 94%, optional 65% ⁇ 85%)
  • the pharmaceutical excipient F1 accounts for 0 ⁇ 2% of the weight of the drug-containing layer
  • the penetration-promoting polymer accounts for 11% to 66% of the weight of the boosting layer (optional 12% to 65%, optionally 20% to 65%, optionally
  • the water-insoluble swelling polymer accounts for 12% to 71% of the weight of the booster layer.
  • the osmotic pressure accelerator accounts for all 10% to 45% of the weight of the booster layer (optional 14% to 42%, further optional 15% to 40%)
  • the pharmaceutical excipient F2 accounts for 0.5% to 2.5% of the weight of the booster layer. %;
  • the weight ratio of the drug-containing layer and the boosting layer is 0.5 ⁇ 2, optionally 0.8 ⁇ 1.6, optionally 0.8 ⁇ 1.5, optionally 0.9 ⁇ 1.5;
  • the weight gain of the controlled release coating layer with release holes is 6% to 25% of the weight of the tablet core, optionally 6% to 21%, optionally 8% to 25%, optionally 8% % ⁇ 15%, optional 10% ⁇ 20%.
  • no release coating film is included between the tablet core and the controlled release coating layer.
  • the osmotic pump controlled release formulation meets one or more of the following characteristics:
  • the booster layer does not contain polyoxyethylene
  • Carbomer is not included in said boost layer
  • the alginate in the penetration-promoting polymer is selected from one or more of sodium alginate, potassium alginate and ammonium alginate.
  • the osmotic pump controlled release formulation meets one or more of the following characteristics:
  • the number of the drug release holes is one or more, and any one of the drug release holes communicates with the drug-containing layer and the osmotic pump controlled release preparation. external;
  • the diameter of the drug release hole is 0.6-1.0 mm.
  • the drug-containing layer meets 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 self-penetrating agents, antistatic agents and lubricants.
  • the drug-containing layer meets one or more of the following characteristics:
  • the penetration aid is selected from one or more of sodium chloride, potassium chloride, sorbitol, xylitol, glucose and sucrose, and optionally sodium chloride;
  • the antistatic agent includes one or more of micropowder silica gel, stearic acid and polyethylene glycol, optionally micropowder silica gel;
  • the lubricant is selected from one or more of magnesium stearate, polyethylene glycol, sodium stearyl fumarate and talc.
  • the penetration-enhancing polymer mainly includes hydroxyethyl cellulose and alginate;
  • the weight ratio of the sum of the weight of the hydroxyethyl cellulose and the alginate in the penetration-promoting polymer is greater than 80%.
  • the boost layer satisfies one or more of the following characteristics:
  • the weight ratio of the hydroxyethyl cellulose and the alginate is 1: (1-60), optionally 1: (1.5-40), further optionally 1: (1.5-25), and further The optional options are 1:(1.5 ⁇ 20), and the further optional options are 1:(1.5 ⁇ 16);
  • the weight proportion of the hydroxyethyl cellulose in the booster layer is 0.4% to 22% (optional 0.5 to 20%).
  • the pharmaceutical excipient F2 is selected from one or more of lubricants, colorants and glidants.
  • the water-insoluble swelling polymer includes at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, and optionally also includes cross-linked carboxylic acid One or more of sodium methylcellulose and crospovidone.
  • the osmotic pressure enhancer is selected from one or more of sodium chloride, potassium chloride, magnesium chloride, sorbitol, xylitol, glucose and sucrose, Optional sodium chloride.
  • the controlled-release coating layer with drug-release holes is composed of a semipermeable controlled-release coating material and optional pharmaceutical excipients F3; wherein the pharmaceutical excipients F3 are plasticizers and One or more porous agents.
  • the osmotic pump controlled release formulation meets one or more of the following characteristics:
  • the semipermeable controlled-release coating film 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 relative to the sum of the weights of the semipermeable controlled-release coating material and the pharmaceutical excipient F3 is 0 to 20%, optionally 1% to 10%, and optionally 1% to 7.4%.
  • the weight gain of the water-soluble coating film is 8% to 20% of the sum of the weight of the tablet core and the controlled release coating layer with drug release holes.
  • the pharmaceutically active ingredient is selected from any one of nifedipine, glipizide, oxybutynin hydrochloride, doxazosin mesylate, and paliperidone.
  • the pharmaceutically active ingredient is nifedipine.
  • the drug-containing layer and the booster layer constitute a bilayer tablet core.
  • the release of the osmotic pump controlled-release preparation is controlled 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 degree at 4h is greater than 4%
  • the release at the 12h point is greater than 40%
  • the release degree at 24h is greater than 90%
  • the release medium is 900 mL of 1% sodium lauryl sulfate phosphate-citrate buffer, 900 mL of artificial intestinal juice without trypsin, 500 mL of 0.1 mol/L hydrochloric acid solution, 900 mL of 0.1 mol /L hydrochloric acid solution or 500mL of 0.2% (w/v) sodium chloride in 0.1mol/L hydrochloric acid solution.
  • an osmotic pump controlled-release composition which is composed of each component of the osmotic pump controlled-release preparation described in the first aspect of this application, and is used to prepare the osmotic pump controlled-release preparation.
  • 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 this application.
  • the preparation method includes the following steps in sequence:
  • the water-soluble coating film is coated.
  • a booster layer composition which is composed of a penetration-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure accelerator and pharmaceutical excipients 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 the first aspect of the application;
  • the penetration-enhancing polymer is a combination of hydroxyethyl cellulose and alginate.
  • the application of the osmotic pump controlled-release preparation described in the first aspect of the present application as an oral controlled-release preparation is provided.
  • the osmotic pump controlled release preparation described in the first aspect of the application or the osmotic pump controlled release composition described in the second aspect of the application, or the booster described in the fourth aspect of the application.
  • preventing and/or treating cardiovascular disease refers to at least one of preventing cardiovascular disease and treating cardiovascular disease.
  • a method for preventing cardiovascular disease includes administering to a subject a prophylactically effective amount of the osmotic pump controlled-release formulation described in the first aspect of the present application, or administering to a subject a preventive effective amount of the present invention.
  • the cardiovascular disease includes at least one of hypertension, coronary heart disease and chronic stable angina.
  • a quality method for cardiovascular diseases includes 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 present invention.
  • the cardiovascular disease includes at least one of hypertension, coronary heart disease and chronic stable angina.
  • an osmotic pump controlled-release preparation for at least one of preventing and treating cardiovascular diseases is provided, and the osmotic pump controlled-release preparation is as defined in the first aspect of the present application.
  • an osmotic pump controlled-release composition for at least one of preventing and treating cardiovascular diseases is provided, and the osmotic pump controlled-release composition is as defined in the first aspect of the present application.
  • the inventor of this application unexpectedly discovered during the process of studying the expansion mechanism of the booster layer: using alginate (such as sodium alginate) and hydroxyethyl cellulose as the main penetration-promoting polymeric excipients, And combined with insoluble swelling polymers (one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, etc.) and osmotic pressure accelerators, etc.
  • the booster layer composition is used to form a tablet core with the drug-containing layer. Each component cooperates with each other and acts synergistically.
  • the osmotic pump controlled-release preparation thus prepared can achieve complete release (final release amount) within 16 to 24 hours.
  • the mechanism is as follows: Based on the interaction between alginate molecular chains and hydroxyethyl cellulose molecular chains, hydroxyethyl cellulose and alginate can form a new three-dimensional network with both high strength and high toughness. -like hydrogel system to improve 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 active ingredients in the drug-containing layer of this product and improve the drug quality. The final release amount helps achieve complete release of the drug.
  • the addition of the penetration-promoting polymer hydroxyethyl cellulose can also improve the adhesion between the particles of each component in the booster layer and improve the tableting force of the double-layer tablet core. It helps to reduce surface damage during the coating process, thereby improving the release stability of osmotic pump controlled-release preparations.
  • the booster layer composition provided in this application is composed of a specific penetration-promoting polymer (optional a combination of alginate and hydroxyethyl cellulose, where the alginate is such as sodium alginate) and a suitable water-insoluble swelling agent.
  • a specific penetration-promoting polymer such as sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone, further such as including sodium carboxymethyl starch and low-substituted At least one of hydroxypropyl cellulose, further such as sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose or a combination of the two
  • osmotic pressure enhancer and other boosting layer excipients pharmaceutically excipient F2
  • the high-strength and high-toughness hydrogel formed by the composition helps to improve the mechanical properties of the hydrogel in the booster layer composition, and promotes the drugs and excipients in the drug-containing layer to release the
  • the drug release hole can release the drug at a uniform speed, and can ensure the uniform release of active ingredients in the drug-containing layer, increase the final release amount of the drug (24-hour point release >90%), and help achieve complete release of the drug.
  • the booster layer composition can be suitable for the preparation and controlled release administration of a variety of active ingredients, including but not limited to glipizide, oxybutynin hydrochloride, doxazosin mesylate and paliperidone, all Stable and controlled release can be achieved in different dissolution media, and drug release is complete.
  • the osmotic pump controlled-release preparation 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, and the product The release of active ingredients is more stable, and the release difference between tablets is small.
  • Figure 1 is a schematic structural diagram of an osmotic pump controlled release preparation in one embodiment of the present application, in which A and B correspond to schematic diagrams with different numbers of drug release holes;
  • Figure 2 is a schematic structural diagram of an osmotic pump controlled-release preparation in one embodiment of the present application
  • Figure 3 is a graph showing the average cumulative release curve of nifedipine controlled-release tablets from Prescription 1 to Prescription 10 in 900 mL medium in the preparation example;
  • Figure 4 is the average cumulative release curve of Comparative Prescription 1 to Comparative Prescription 8 nifedipine controlled-release tablets in 900 mL medium in the preparation example;
  • Figure 5 is a microscopic observation view of the booster layer of the nifedipine controlled-release tablets of Prescription 1 and Comparative Prescription 2 in the preparation example;
  • A is a cross-sectional view of the booster layer of Tablet 1 of Comparative Prescription 2;
  • B is the Comparative Prescription 2
  • C is the cross-sectional view of the boosting layer of tablet 1 of prescription 1;
  • D is the cross-sectional view of the boosting layer of tablet 2 of prescription 1;
  • Figure 6 is a release curve diagram of the glipizide controlled-release tablet of Prescription 11 in the preparation example
  • Figure 7 is a release curve diagram of Prescription 12 oxybutynin hydrochloride controlled-release tablets in the preparation example
  • Figure 8 is a release curve diagram of doxazosin mesylate controlled-release tablets of Prescription 13 in the preparation example
  • Figure 9 is a release curve diagram of prescription 14 paliperidone controlled-release tablets in the preparation example.
  • Figure 10 is a release curve diagram of nifedipine controlled-release tablets in 100 mL medium of Preparation Example Prescription 1 and Comparative Prescription 2;
  • Figure 11 is a release curve diagram of Prescription 2 nifedipine controlled-release tablets in 5%, 10%, 20% and 40% ethanol release media in the preparation example;
  • Figure 12 is a release curve diagram of comparative prescription 2 nifedipine controlled-release tablets in 5%, 10%, 20% and 40% ethanol release media in the preparation example;
  • Figure 13 is a release curve diagram of nifedipine controlled-release tablets of prescription 2 and comparative prescription 3 in artificial intestinal fluid in the preparation example;
  • Figure 14 is a blood drug concentration-time curve chart after oral administration of nifedipine controlled-release tablets to dogs in Preparation Example 6 and Comparative Prescription 3;
  • Figure 15 shows the results of the friability test of controlled-release tablets with different prescriptions in the coating pot.
  • A, and/or, B, and/or, C, and/or, D including any one of A, B, C, and D. (That is, technical solutions that are all connected by "logical OR"), including any and all combinations of A, B, C, and D, including any two or any three of A, B, C, and D.
  • the combination also includes four combinations of A, B, C, and D (that is, technical solutions that are all connected by "logical AND”).
  • Another example is “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”.
  • first”, “second”, “third” and “fourth” etc. are for descriptive purposes only and shall not be understood as indicating or implying relative importance or quantity, nor shall they be understood as implicitly indicating the importance or quantity of indicated technical features.
  • first”, “second”, “third”, “fourth”, etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation of quantity.
  • 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.
  • the temperature parameters in this application are allowed to be treated at a constant temperature, and are also allowed to vary within a certain temperature range. It should be understood that the thermostatic treatment described allows the temperature to fluctuate within the accuracy of the instrument control. It is allowed to fluctuate within the range of ⁇ 5°C, ⁇ 4°C, ⁇ 3°C, ⁇ 2°C and ⁇ 1°C.
  • room temperature generally refers to 4°C to 35°C, preferably 20°C ⁇ 5°C. In some embodiments of the present application, room temperature refers to 20°C to 30°C.
  • “approximately” means within a certain range above and below the number.
  • the fluctuation range may vary depending on the type and value of the number. This fluctuation range can be reasonably confirmed based on the accuracy of the test or measurement method, for example, "about 10mg” It can be expressed as selected from 10 ⁇ 0.4mg, etc.
  • references to "molecular weight" of a polymer refer to the weight average molecular weight unless otherwise stated.
  • any step may include multiple sub-steps or multiple stages. These sub-steps or stages are not necessarily executed at the same time, but may be executed at different times, and the order of execution is not necessarily sequential. It can be performed in turn or alternately with other steps or sub-steps or parts of stages of other steps or simultaneously.
  • pharmaceutical excipients should be understood as pharmaceutically acceptable excipients that comply with current management standards for pharmaceutical excipients.
  • pharmaceutically acceptable means one that is suitable for administration to a patient within the scope of reasonable medical judgment and is proportionate to a reasonable benefit/risk ratio.
  • patient refers to an animal, optionally a mammal, preferably a human.
  • mammal mainly refers to warm-blooded vertebrate mammals, including but not limited to: cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, cattle, sheep, horses and humans.
  • 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 booster layer that is the same as the hydrophilic polymer carrier.
  • Use excipients; “Pharmaceutical excipients F3” are pharmaceutical excipients in the controlled-release coating layer with drug release holes, which can be plasticizers and/or porogens (i.e. one of plasticizers and porogens or variety).
  • release at XX time point means the cumulative release amount from the start of release (0h) to XX time point as a percentage of the total theoretical release amount.
  • release at 4h can represent the cumulative release from 0 to 4h, which can be expressed as a percentage.
  • an osmotic pump controlled-release preparation which includes the following structure arranged in sequence from the inside to the outside: a tablet core including a drug-containing layer and a booster layer, and a controlled-release coating layer with drug release holes , optional water-soluble coating film; wherein, the drug-containing layer is connected 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-release hole; the drug-containing layer contains active pharmaceutical ingredients , the booster layer includes a penetration-promoting polymer, and the penetration-promoting polymer contains hydroxyethyl cellulose and alginate.
  • the formula is simple and can accurately control the stable release duration and release degree of the drug without the need for an isolation film. For example, the stable release of the drug can be controlled from 16 to 24 hours, and the release degree in 24 hours can be greater than 90%.
  • the osmotic pump controlled release preparation includes a double-layer tablet core structure, and further, the double-layer tablet core structure includes a drug-containing layer and a booster layer.
  • the tablet core including a drug-containing layer and a booster layer is a double-layer tablet core structure.
  • the tablet core including the drug-containing layer and the booster layer is composed of the drug-containing layer and the booster layer.
  • the drug release hole is located only on one side of the drug-containing layer, that is, on one side.
  • an osmotic pump controlled-release preparation which includes the following structure arranged in sequence from the inside to the outside: a double-layer tablet core including a drug-containing layer and a booster layer, and a controlled-release coating layer with drug release holes. , optional water-soluble coating film; wherein, the drug release hole is connected to the drug-containing layer and the outside of the osmotic pump controlled-release preparation, and the drug release hole is located on one side of the drug-containing layer; the booster layer is located on the drug-containing layer away from the drug release hole on one side; the drug-containing layer contains active pharmaceutical ingredients, the boosting layer includes a penetration-promoting polymer, and the penetration-promoting polymer contains hydroxyethyl cellulose and alginate.
  • the formula is simple and can accurately control the stable release duration and release degree of the drug without the need for an isolation film. For example, the stable release of the drug can be controlled from 16 to 24 hours, and the release degree in 24 hours can be greater than 90%.
  • an osmotic pump controlled-release preparation which includes the following structures arranged in sequence from the inside to the outside:
  • a tablet core including a drug-containing layer and a booster layer
  • a controlled release coating layer with drug release holes A controlled release coating layer with drug release holes
  • the water-soluble coating film can be used as a moisture-proof film and/or an aesthetic coat, that is, it can be used as at least one of a moisture-proof film and an aesthetic coat);
  • the drug-release 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-release hole;
  • the drug-containing layer is composed of active pharmaceutical ingredients, hydrophilic polymer carrier and pharmaceutical excipient F1; wherein, pharmaceutical excipient F1 is a pharmaceutical excipient different from the hydrophilic polymer carrier;
  • the boosting layer is composed of a penetration-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure accelerator and pharmaceutical excipients F2; wherein the penetration-promoting polymer includes hydroxyethyl cellulose and alginate; the water-insoluble swelling polymer includes carboxylic acid Sodium methyl starch, low substituted hydroxypropyl One or more of cellulose, croscarmellose sodium and crospovidone; among them, pharmaceutical excipient F2 is different from penetration-promoting polymers, water-insoluble swelling polymers and osmotic pressure accelerators of medicinal excipients.
  • portion of the controlled release coating layer adjacent to the booster layer is not provided with drug release holes.
  • the osmotic pump controlled-release preparation can control the stable release of the drug within 16 to 24 hours, and the release rate at the 24-hour time point can be greater than 90%. It can achieve clinical therapeutic effects at the frequency of once-daily administration. Each administration The effect lasts for 24 hours.
  • the structure of the osmotic pump controlled release preparation can be seen in Figure 1, where A and B respectively correspond to osmotic pump controlled release tablets with different numbers of release holes.
  • the osmotic pump controlled-release preparation shown in A and B in Figure 1 includes the following structures arranged in sequence from the inside to the outside: a tablet core including a drug-containing layer 1 and a booster layer 2; and a controlled-release coating layer with drug release holes 4 3; Among them, the drug release hole 4 is connected to the outside of the drug-containing layer 1 and the osmotic pump controlled release preparation; the booster layer 2 is located on the side of the drug-containing layer away from the drug release hole 4.
  • the structure of the osmotic pump controlled release preparation can be seen in Figure 2, which includes an osmotic pump controlled release tablet including a water-soluble coating film.
  • the osmotic pump controlled-release preparation shown in Figure 2 includes the following structure arranged in sequence from the inside to the outside: a tablet core including a drug-containing layer 1 and a booster layer 2, a controlled-release coating layer 3 with drug release holes 4, and a water-soluble Coating film 5; wherein, the drug release hole 4 communicates with the outside of the drug-containing layer 1 and the osmotic pump controlled release preparation; the booster layer 2 is located on the side of the drug-containing layer away from the drug release hole 4.
  • nifedipine 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 (optional 40% ⁇ 95%, optionally 40% ⁇ 94%, optionally 65% ⁇ 96%, optionally 65% ⁇ 94%, optionally 65% ⁇ 85%)
  • pharmaceutical excipients F1 accounts for 0 ⁇ 2% of the weight of the drug-containing layer
  • the penetration-promoting polymer accounts for 11% to 66% of the weight of the booster layer (optional 12% ⁇ 65%, optional 20% ⁇ 65%, optional 11% ⁇ 50% %, optionally 20% to 50%, optionally 20% to 40%), the water-insoluble swelling polymer accounts for 12% to 71% of the weight of the booster layer (optional 13% to 70%, further Optional 15% ⁇ 60%, further optional 20% ⁇ 50%, further optional 20% ⁇ 40%), the osmotic pressure accelerator accounts for 10% ⁇ 45% of the weight of the booster layer (optional 14% to 42%, further optionally 15% to 40%), and the medicinal excipient F2 accounts for 0.5% to 2.5% of the weight of the booster layer;
  • the weight ratio of the drug-containing layer and the boosting layer is 0.5 ⁇ 2, optionally 0.8 ⁇ 1.6, optionally 0.8 ⁇ 1.5, optionally 0.9 ⁇ 1.5;
  • the weight gain of the controlled release coating layer with release holes is 6% to 25% of the weight of the tablet core, optionally 6% to 21%, optionally 8% to 25%, optionally 8% to 15% , and optionally 10% to 20%.
  • the tablet core includes a drug-containing layer and a booster layer.
  • the tablet core is composed of a drug-containing layer and a booster layer.
  • the tablet core has a double-layer core structure.
  • the drug-containing layer and the booster layer form a bilayer tablet core, as shown in Figure 1.
  • the weight ratio of the drug-containing layer and the boosting layer is 0.5-2.
  • the weight ratio of the drug-containing layer and the boosting 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 and the boosting 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.
  • the penetration-enhancing polymer includes hydroxyethyl cellulose and alginate
  • the water-insoluble swelling polymer is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and Any one of crospovidone or a combination thereof.
  • the penetration-enhancing polymer is hydroxyethyl cellulose and alginate
  • the water-insoluble swelling polymer includes sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and At least one of crospovidones.
  • the penetration-enhancing polymer is hydroxyethyl cellulose and alginate
  • the water-insoluble swelling polymer is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and Any one or combination of crospovidones.
  • the penetration-promoting polymer includes hydroxyethyl cellulose and alginate
  • the water-insoluble swelling polymer is any one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose or a combination thereof.
  • the penetration-promoting polymer is hydroxyethyl cellulose and alginate
  • the water-insoluble swelling polymer includes at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.
  • the penetration-promoting polymer is hydroxyethyl cellulose and alginate
  • the water-insoluble swelling polymer is any one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose or a combination thereof.
  • the alginate in the penetration-promoting polymer may be selected from one or more of sodium alginate, potassium alginate, and ammonium alginate.
  • the drug-containing layer is a structural layer that includes active pharmaceutical ingredients.
  • the drug-containing layer is composed of active pharmaceutical ingredients, a hydrophilic polymer carrier and a pharmaceutical excipient F1; further, the pharmaceutical excipient F1 is a pharmaceutical excipient different from the hydrophilic polymer carrier.
  • the pharmaceutical active 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 (optional 40% ⁇ 95%, optionally 40% ⁇ 94%, optionally 65% ⁇ 96%, optionally 65% ⁇ 94%, optionally 65% ⁇ 85%)
  • pharmaceutical excipients F1 accounts for 0 to 2% of the weight of the drug-containing layer.
  • the pharmaceutical 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 ranges: 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% ⁇ 20%, 5% ⁇ 30%, 5% ⁇ 25%, 5% ⁇ 20%, 7% ⁇ 30%, 7% ⁇ 25%, 7% ⁇ 20%, 8% ⁇ 30% , 8% ⁇ 25%, 8% ⁇ 20%, etc.
  • the amount of hydrophilic polymeric carrier used in the drug-containing layer depends on the composition of the tablet core and the desired 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 of the following percentages or any two ranges: 65 %, 66%, 67%, 68%, 69%, 70%, 72%, 74%, 75%, 76%, 78%, 80%, 82%, 84%, 85%, 86%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, etc., can also be selected from 40% ⁇ 95%, 40% ⁇ 94%, 65% ⁇ 96%, 65% ⁇ 94%, 65% ⁇ 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%
  • the pharmaceutical excipient F1 accounts for 0 to 2% of the weight of the drug-containing layer, and can also be selected from any one of the following percentages or any two ranges: 0.3%, 0.33 %, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, .75%, .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., 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% ⁇ 0.9%, 0.3% ⁇ 0.8%, 0.4% ⁇ 0.8%, etc.
  • the pharmaceutically active ingredient is selected from any one of nifedipine, glipizide, oxybutynin hydrochloride, doxazosin mesylate, and paliperidone.
  • the pharmaceutically active ingredient is nifedipine.
  • the hydrophilic polymer carrier may include, but is not limited to, povidone, copovidone, or combinations thereof. In some embodiments, in the drug-containing layer, the hydrophilic polymer carrier is povidone, copovidone, or a combination thereof.
  • the hydrophilic polymer carrier may include, but is not limited to, povidone K90, copovidone VA64, or combinations 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.
  • the drug-containing layer may also contain other drug-containing layer excipients available in the field (denoted as pharmaceutical excipients F1).
  • pharmaceutical excipient F1 is a pharmaceutical excipient in the drug-containing layer that is different from the hydrophilic polymer carrier.
  • pharmaceutical excipients F1 may include, without limitation, one or more of penetration aids, antistatic agents, and lubricants.
  • the pharmaceutical excipient F1 is selected from one or more of an exudative agent, an antistatic agent and a lubricant.
  • the penetration aid is selected from one or more of sodium chloride, potassium chloride, sorbitol, xylitol, glucose and sucrose, and may further be sodium chloride.
  • the antistatic agent in the drug-containing layer, includes one or more of micronized silica gel, stearic acid and polyethylene glycol, and may further be micronized silica gel.
  • the lubricant in the drug-containing layer, 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.
  • the boosting layer as a polymer sustained-release material layer with its own expansion and propulsion effects, can boost and regulate the release rate.
  • the booster layer of the present application usually contains one or more sustained-release polymers, osmotic pressure enhancers and other booster layer auxiliary materials.
  • the sustained-release polymer in the booster layer is an important component of the controlled-release preparation of the osmotic pump. In this application, it usually includes an osmotic-promoting polymer and an insoluble swelling polymer.
  • the boosting layer is composed of a penetration-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure enhancer and pharmaceutical excipients F2; further, the penetration-promoting polymer includes hydroxyethyl cellulose and alginate; Further, the water-insoluble swelling polymer includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone; further, Pharmaceutical excipient F2 is a pharmaceutical excipient different from penetration-promoting polymers, water-insoluble swelling polymers and osmotic pressure accelerators.
  • the penetration-promoting polymer in the booster layer of the present application is one of the key components to achieve controlled expansion of the booster layer.
  • penetration-enhancing polymers usually include carbomer, polyoxyethylene, povidone, copovidone, hypromellose, hydroxypropylcellulose or combinations thereof.
  • Carbomer and polyoxyethylene are the most commonly used penetration-enhancing polymers in the booster layer of commercially available osmotic pump controlled-release preparations.
  • the inventor of the present application found that due to its low melting point, polyoxyethylene is prone to produce "curling” due to heat generation during high-speed tableting production. This kind of "curling" with raised edges can easily cause the phenomenon of "curling” after coating.
  • the inventor of the present application found that due to the strong electrostatic effect of carbomer, the powder itself is easy to agglomerate, and the granulation process is easy to agglomerate and difficult to Mixed with other excipients, it is difficult to control the uniformity of the tablets during the production process, and there are some problems with the stability of the release of the final product.
  • the inventor of this application found through experimental exploration that if the above-mentioned penetration-promoting polymer and insoluble swelling polymer are used in combination, the production process of granulation and tableting will have many disadvantages, higher production requirements, and uneven mixing of the product. It is easy to 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.
  • the inventor of this application unexpectedly discovered during the process of studying the expansion mechanism of the booster layer: using alginate (such as sodium alginate) and hydroxyethyl cellulose as the main penetration-promoting polymeric excipients, And combined with insoluble swelling polymers (one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, etc.) and osmotic pressure accelerators, etc.
  • the booster layer composition is used to form a tablet core with the drug-containing layer. Each component cooperates with each other and acts synergistically.
  • the osmotic pump controlled-release preparation thus prepared can achieve complete release (final release amount) within 16 to 24 hours.
  • the penetration-promoting polymer accounts for 11% to 66% of the weight of the boosting layer (optional 12% to 65%, optionally 20% to 65%, optionally Optional 11% ⁇ 50%, optional 20% ⁇ 50%, optional 20% ⁇ 40%), water-insoluble swelling polymer accounts for 12% ⁇ 71% of the weight of the booster layer (optional 13% ⁇ 70%, further optionally 15% ⁇ 60%, further optionally 20% ⁇ 50%, further optionally 20% ⁇ 40%), the osmotic pressure accelerator accounts for 10% of the weight of the booster layer % ⁇ 45% (optional 14% ⁇ 42%, further optional 15% ⁇ 40%), medicinal excipient F2 accounts for 0.5% ⁇ 2.5% of the weight of the booster layer.
  • the penetration-promoting polymer accounts for 11% to 66% of the weight of the booster layer, and can also be selected from any one of the following percentages or any two ranges: 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, etc., and can also be selected from 11% to 50%, 11% to 40%, Suitable ranges include 12% to 65%, 20% to 65%, 11% to 50%, 20% to 50%, 20% to 40%, and the like.
  • the penetration-enhancing polymer in the booster layer, consists essentially of hydroxyethyl cellulose and alginate.
  • the "mainly containing" means that the weight ratio is greater than 80%. That is, in the boosting layer, the weight of the sum of the weight of hydroxyethyl cellulose and alginate (such as sodium alginate) in the penetration-promoting polymer is greater than 80%.
  • the weight ratio of the sum of the weight of hydroxyethyl cellulose and alginate (such as sodium alginate) in the penetration-promoting polymer can 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.
  • the alginate in the penetration-promoting polymer may be selected from one or more of sodium alginate, potassium alginate, and ammonium alginate.
  • the inventor of this application speculates that the mechanism is as follows: Based on the interaction between the molecular chain of alginate (such as sodium alginate) and the macromolecular chain of hydroxyethyl cellulose, the coordination of hydroxyethyl cellulose and alginate (such as sodium alginate)
  • alginate such as sodium alginate
  • the use can form a new three-dimensional network hydrogel system with both high strength and high toughness, improve the mechanical properties of the booster layer composition (including good compressibility and tensile properties), and form a high-strength hydrogel that can synergize Promote the uniform release of active ingredients in the drug-containing layer of this product, increase the final release amount of the drug, and help achieve complete release of the drug.
  • the penetration-enhancing polymer consists of hydroxyethyl cellulose and alginate.
  • the viscosity range of alginate that can be used in this application can be selected from but not limited to 20cps to 1000cps, such as any one of the following viscosity values or an interval composed of any two 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 that can be used in the present application can be selected from a suitable range from the following ranges: 100cps ⁇ 1000cps, 100cps ⁇ 800cps, 100cps ⁇ 700cps, 140cps ⁇ 650cps, 140cps ⁇ 600cps, 143cps ⁇ 600cps, etc.
  • the alginate in the penetration-enhancing polymer is sodium alginate.
  • the penetration-enhancing polymer consists of hydroxyethyl cellulose and sodium alginate.
  • the alginate (such as sodium alginate) used in this application is a natural product generated from alginic acid and minerals in seawater.
  • the main source is kelp or macroalgae in brown algae. It is composed of mannuronic acid (M) and ancient A mixed polysaccharide structure composed of urouronic acid (G).
  • M mannuronic acid
  • G urouronic acid
  • the gel produced by high G-type alginate is hard but brittle; the gel produced by high M-type alginate is the opposite, flexible but low in hardness. Adjusting the two ratios can produce gels of different strengths.
  • the sodium alginate used in this application can be used in food and medicine and has good safety.
  • the viscosity range of sodium alginate that can be used in this application can be selected from but not limited to 20cps to 1000cps, such as any one of the following viscosity values or an interval composed of 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, 900cps, 1000cps, etc.
  • the viscosity of the sodium alginate that can be used in this application can be selected from a suitable range in the following ranges: Gauge: 100cps ⁇ 1000cps, 100cps ⁇ 800cps, 100cps ⁇ 700cps, 140cps ⁇ 650cps, 140cps ⁇ 600cps, 143cps ⁇ 600cps, etc.
  • the sodium alginate in the booster layer of this application slowly swells into a highly viscous gel when exposed to water, which helps control the swelling rate of the insoluble polymer and achieve uniform release.
  • Potassium alginate used in this application is a milky white to light yellow powder or granule. It has good hydrophilicity, fluidity, thickening and gelling properties. Its strength is better than sodium alginate under the same conditions. As Hydrophilic colloid, easily soluble in water to form a viscous solution. Potassium alginate used in this application can be used in one or more aspects of food, health products and medicines.
  • the viscosity range of potassium alginate used in this application can be selected from but not limited to 20cps to 1000cps, such as any one of the following viscosity values or an interval composed of 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, 900cps, 1000cps, etc.
  • the viscosity of the potassium alginate that can be used in the present application can be selected from a suitable range from the following ranges: 100cps ⁇ 1000cps, 100cps ⁇ 800cps, 100cps ⁇ 700cps, 140cps ⁇ 650cps, 140cps ⁇ 600cps, 143cps ⁇ 600cps, etc.
  • the ammonium alginate used in this application is a light yellow to brown amorphous powder or granule. It has good hydrophilicity, thickening and gelling properties. As a hydrophilic colloid, it is easily soluble in water to form a viscous consistency. solution.
  • the potassium alginate used in this product can be used in one or more aspects of food, health products and pharmaceuticals.
  • the viscosity range of ammonium alginate that can be used in this application can be selected from but not limited to 20cps to 800cps, such as any one of the following viscosity values or an interval composed of 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 the following suitable ranges: 100cps ⁇ 800cps, 100cps ⁇ 700cps, 140cps ⁇ 650cps, 140cps ⁇ 600cps, 143cps ⁇ 600cps, etc.
  • the hydroxyethyl cellulose used in this application is a non-ionic water-soluble polymer material, a polymer that can absorb water and swell quickly. Hydroxyethyl cellulose gels quickly when exposed to water.
  • hydroxyethyl cellulose can be used as tablet binder, matrix material, film coating material, etc. in pharmaceutical preparations, but there has been no relevant research on using hydroxyethyl cellulose as a permeation-enhancing polymer for the booster layer. The inventor of the present application accidentally used hydroxyethyl cellulose in the booster layer and achieved surprisingly good results.
  • the weight ratio of hydroxyethyl cellulose and alginate is 1: (1-60), and further can be 1: (1.5-40), A further step may be 1:(1.5 ⁇ 25), a further step may be 1:(1.5 ⁇ 20), and a further step may be 1:(1.5 ⁇ 16).
  • the weight ratio of hydroxyethyl cellulose and alginate can also be selected from any one or two of the following intervals: 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. .
  • the weight proportion of hydroxyethyl cellulose in the booster layer is 0.4% to 22%, and can further be 0.5 to 20%. It can also be selected from any one or two of the following percentages: Interval: 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 booster layer can also be selected from any of the following ranges Suitable range: 1% ⁇ 22%, 1% ⁇ 20%, 2% ⁇ 22%, 2% ⁇ 20%, 2.5% ⁇ 22%, 2.5% ⁇ 20%, 4% ⁇ 22%, 4% ⁇ 20% , 5% ⁇ 22%, 5% ⁇ 20%, 0.5% ⁇ 15%, 1% ⁇ 15%, 2% ⁇ 15%, 2.5% ⁇ 15%, 4% ⁇ 15%, 5% ⁇ 15%, 0.5 % ⁇ 10%, 1% ⁇ 10%, 2% ⁇ 10%, 2.5% ⁇ 10%, 4% ⁇ 10%, 5% ⁇ 10%, etc.
  • the boost layer satisfies one or more of the following characteristics:
  • the weight ratio of hydroxyethyl cellulose and alginate is 1: (1-60), further can be 1: (1.5-40), and further can be 1: (1.5 ⁇ 25), further it can be 1:(1.5 ⁇ 20), still further it can be 1:(1.5 ⁇ 16), you can also refer to the appropriate range or value in the aforementioned weight ratio;
  • the weight ratio of hydroxyethyl cellulose in the booster layer is 0.4% to 22% (further 0.5 ⁇ 20%). You can also refer to the appropriate value or range in the aforementioned weight ratio. .
  • a permeating polymer combination of alginate (such as sodium alginate) and hydroxyethyl cellulose provides a permeating polymer that achieves 24-hour More than 90% release; in another embodiment (such as Preparation Example Recipe 2 and Experimental Example 4), the penetration of alginate (which can further be sodium alginate) and hydroxyethylcellulose in this application is used Compared with hypromellose K15M and/or copovidone (either one or a combination of both), the controlled-release tablets prepared by the polymer combination have a more complete final release amount of the drug in the technical solution provided by this application.
  • the release degree of prescription 2 tablets in the preparation example at the 24-hour time point is 102.7%
  • the 24-hour release degree of the comparison prescription 1 tablet (combination of hypromellose K15M and copovidone) in the preparation example is only is 86.7%.
  • hydroxyethyl cellulose can also increase the adhesion between the excipient 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. properties, which is conducive to achieving high-speed tableting and improving production efficiency.
  • the insoluble swelling polymer in the booster layer of the present application can expand rapidly when exposed to water, thereby boosting drug release.
  • the water-insoluble expanded polymer accounts for 12% to 71% of the weight of the booster layer, based on the total weight of the booster layer, It 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., can also be selected from 12% ⁇ 60%, 12% ⁇ 50%, 12% ⁇ 40%, 13% ⁇ 70%, 13% ⁇ 60%, 13% ⁇ 50%, 13% ⁇ 40%, 15% ⁇ 70%, 15% ⁇ 60%, 15% ⁇ 50%, 15% ⁇ 40%, 20% ⁇ 70%, 20% ⁇ 60%, 20% ⁇ 50%, 20% ⁇ 40% wait.
  • the water-insoluble swelling polymer includes one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone.
  • the water-insoluble swelling polymer is any one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone, or a combination thereof. thereof); "combination thereof” means any suitable combination of the aforementioned water-insoluble swelling polymers.
  • the water-insoluble swelling polymer includes at least one of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose. Further, the water-insoluble swelling polymer optionally includes one or more of croscarmellose sodium and crospovidone.
  • the water-insoluble swelling polymer includes sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.
  • the water-insoluble swelling polymer is a combination of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.
  • low-substituted hydroxypropyl cellulose can be produced by reacting alkaline cellulose and propylene oxide under high temperature and high pressure.
  • the hydroxypropyl substitution rate may be 5% to 16%, further such as 7% to 16%.
  • the booster layer of the present application contains an osmotic pressure accelerator.
  • Osmotic pressure accelerators such as sodium chloride and other inorganic salt osmotic pressure accelerators
  • the viscosity of the hydroxyethyl cellulose used in this application is not affected by the sodium chloride content and has good salt resistance, which can ensure that the hydroxyethyl cellulose forms a stable gel system after absorbing water in the gastrointestinal tract. Achieve smooth release of drugs.
  • the osmotic pressure enhancer accounts for 10% to 45% of the weight of the boosting layer, further may be 14% to 42%, further may be 15% to 40%, and more Furthermore, it may be 15%-35%, and further, it may be 15%-30%. It can also be selected from any one of the following percentages or any two intervals: 15%, 16%, 18%, 20%, 25%, 30%, 35%, 36%, 38%, 40%, 41%, etc. .
  • the osmotic pressure accelerator is an inorganic salt osmotic pressure accelerator, which may further be sodium chloride.
  • 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 chlorine.
  • sodium chloride sodium chloride.
  • the osmotic pressure enhancer is sodium chloride.
  • sodium chloride has stable physical and chemical properties, good water solubility and good biological safety.
  • the booster layer may also include other booster layer excipients available in the field (denoted as pharmaceutical excipients F2).
  • pharmaceutical excipients F2 is the same pharmaceutical excipient as the hydrophilic polymer carrier in the booster layer.
  • pharmaceutical excipients F2 may include, without limitation, one or more of lubricants, colorants, etc.
  • the pharmaceutical excipient F2 is selected from one or more of lubricants, colorants and glidants.
  • the pharmaceutical excipient F2 accounts for 0.5% to 2.5% of the weight of the boosting layer, further 0.5% to 2%, further such as 0.5% to 1.5%. It can also be selected from any one of the following percentages or any two intervals: 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.
  • the addition of lubricant can improve the fluidity of the drug-containing layer and booster layer particles during the high-speed tableting process, and improve the content and content uniformity of the pharmaceutical preparation.
  • the lubricant in the booster layer may be selected from, but is not limited to, one or more of stearic acid, magnesium stearate, sodium stearyl fumarate, talc, paraffin, etc.
  • the use of colorants can make it easy to distinguish the drug-containing layer and the booster layer of the drug, and the choice of color does not affect the actual use and effect of the present application.
  • the colorant in the boost layer may be selected from, but is not limited to, one or more of iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black, and the like.
  • glidants mainly improves the fluidity of powders or granules, which is beneficial to the stable control of the tableting process.
  • the selection range of glidants in the booster layer includes but is not limited to micronized silica gel.
  • a release coating film is not included between the tablet core and the controlled release coating layer. In some embodiments, a release coating film is not included between the drug-containing layer and the booster layer.
  • the osmotic pump controlled-release preparation provided in this application can achieve a high drug release rate (more than 90% release at 24 hours) without setting up an isolation coating film.
  • polyoxyethylene is not included in the booster layer. It can overcome the heat-sensitive disadvantages of polyoxyethylene in traditional booster layers.
  • carbomer is not included in the boost layer. It can avoid defects such as unstable inter-tablet release caused by uneven mixing and granulation.
  • a mold can be used to compress each component of the drug-containing layer and each component of the booster layer into a tablet core, such as a double-layer tablet core structure.
  • the controlled-release coating layer also called the controlled-release coating film
  • the controlled-release coating film is a key component of the controlled-release composition of the osmotic pump.
  • the existence of the controlled-release coating film can allow water to penetrate through, while the penetration aids and osmotic polymers It cannot pass through, thus ensuring a relatively independent microenvironment inside the chip chip.
  • 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%, optionally 8% to 25%, optionally 8% to 15%, optional 10% to 20%. It can also be selected from any one of the following percentages or any two intervals: 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, etc.
  • the controlled release coating layer with drug release holes mainly includes cellulose acetate or a premixed coating powder containing cellulose acetate (such as Opadry CA), but is not limited to these.
  • the controlled release coating layer with drug release holes is composed of a semipermeable controlled release coating film material and optional controlled release coating layer excipients (recorded as pharmaceutical excipients F3); further, pharmaceutical excipients F3 It can be a plasticizer and/or a porogen.
  • the pharmaceutical excipient F3 can be a plasticizer, a porogen, or a combination of a plasticizer and a porogen.
  • the semipermeable controlled-release coating material is cellulose acetate or a premixed coating powder containing cellulose acetate.
  • the porogen and/or plasticizer can increase the moisture permeability of the controlled release coating film material.
  • the pharmaceutical excipient F3 is a plasticizer and/or a porogen (that is, one or a combination of both plasticizers and porogens), and
  • the weight proportion of pharmaceutical excipient F3 in the dry film is 0-20%, further can be 1-10%, further can be 1%-7.4%, and further can be 1-7%.
  • the "dry coating" of the controlled-release coating film refers to the film after the controlled-release coating material and F3 excipients are dissolved in a solvent, coated to the tablet core through a coating process, and then the solvent is removed through a drying process. The film formed.
  • the main components of the "dry film” of the controlled-release coating film are semi-permeable controlled-release coating materials and F3 excipients.
  • the dry coating film of the controlled release coating film is composed of a semipermeable controlled release coating film material and pharmaceutical excipient F3.
  • the weight ratio of the pharmaceutical excipient F3 relative to the sum of the weights of the semipermeable controlled-release coating material and the pharmaceutical excipient F3 can be 0 to 20%, further can be 1% to 10%, and further can be 1 % ⁇ 7.4%, further can be 1% ⁇ 7%.
  • the weight proportion of the pharmaceutical excipient F3 in the dry film can also be selected from any of the aforementioned suitable pharmaceutical excipients.
  • the porogen used in the controlled release coating layer can be selected from, but not limited to, glycerin, povidone, copovidone, propylene glycol, polyethylene glycol, and the like.
  • 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.
  • pharmaceutical excipient F3 is selected from one or more of polyethylene glycol, diethyl phthalate, triethyl citrate, triacetin, dibutyl sebacate, etc. .
  • the solvent suitable for the controlled-release coating layer of the present application can be selected from, but not limited to, acetone, water, ethanol, methanol, isopropyl alcohol and dichloromethane. one or more of them.
  • the controlled-release coating film can be dried in a high-efficiency coating pan by spraying and then wrapped on the tablet core.
  • the controlled release coating layer has at least one channel (which can be recorded as a drug release hole) connecting the drug-containing layer and the outside, so that the drug in the drug-containing layer can be released.
  • the drug release holes can be prepared by mechanical drilling or laser drilling.
  • the number of drug release holes is one or more, and further, any drug release hole communicates with the drug-containing layer and the outside of the osmotic pump controlled release preparation.
  • the diameter of any drug release hole is 0.6-1.0 mm.
  • Non-limiting examples include 0.6mm, 0.7mm, 0.8mm, 0.9mm, 1.0mm, etc.
  • the coating film in this application is a water-soluble coating film.
  • the water-soluble coating film is an optional structure and can be used as a moisture-proof clothing film and/or an aesthetic outerwear, a moisture-proof clothing film, an aesthetic outerwear, or both a moisture-proof clothing film and an aesthetic outerwear at the same time.
  • the moisture-proof coating film and the aesthetic outer coating can be provided by the same water-soluble coating film, or they can be provided by different water-soluble coating films.
  • the moisture-proof garment membrane and the aesthetic outer garment are provided separately, and in some embodiments, the aesthetic outer garment is located on the outside of the moisture-proof garment membrane.
  • the moisture-proof clothing membrane is an optional structure and is dispensable.
  • the moisture-proof coating film When the moisture-proof coating film is provided, it can be stacked with the controlled-release coating layer with drug-release holes, and be located on the side surface of the controlled-release coating layer away from the drug-containing layer.
  • the aesthetic outerwear is an optional structure and is dispensable.
  • an aesthetic coat it can be stacked with the controlled release coating layer with drug release holes and located on the side surface of the controlled release coating layer away from the drug-containing layer.
  • the weight gain of the water-soluble coating film is 8% to 20% of the sum of the weight of the tablet core and the controlled release coating layer with release holes, and can also be selected from any one or two of the following percentages: Intervals composed of various percentages: 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc. You can also choose from 10% ⁇ 20%, 10% ⁇ 18%, etc.
  • the water-soluble coating film can improve the appearance of the preparation to increase the patient's compliance with medication, and can also provide color identification.
  • the components of the water-soluble coating film can be selected from one or more of colorants, plasticizers, opacifiers, anti-sticking agents, solvents, etc.
  • the moisture-proof clothing film may include Opadry, Chromium, and other coating powders that can form moisture-proof clothing, which are well known to those skilled in the art.
  • the controlled release coating layer and the water-soluble coating film are stacked in sequence, as shown in Figure 2.
  • the weight gain of the water-soluble coating film is 5 to 20% of the sum of the weight of the tablet core and the controlled-release coating layer with release holes.
  • the release of the osmotic pump controlled-release preparation is controlled at 37°C and 100 rpm, and 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 degree at 4 hours is greater than 4%;
  • the release at the 12 hour point is greater than 40%
  • the release degree at 24 hours is greater than 90%
  • the release medium can be 900 mL of 1% sodium dodecyl sulfate phosphate-citrate buffer, 900 mL of artificial intestinal juice without trypsin, 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.
  • the osmotic pump controlled-release preparation may contain any of the aforementioned suitable pharmaceutical active ingredients, including but not limited to any of nifedipine, glipizide, oxybutynin hydrochloride, doxazosin mesylate, and paliperidone.
  • hydrochloric acid solution refers to a solution containing hydrochloric acid using water as a solution.
  • An aqueous hydrochloric acid solution composed of hydrochloric acid and water can be selected.
  • the release behavior of the pharmaceutically active ingredient in the osmotic pump controlled-release preparation satisfies one or more of the following release properties:
  • the release degree at 4 hours is 4% to 40%
  • the release at the 12-hour time point is 40% to 85%;
  • the release at 24 hours is greater than 90%.
  • the release behavior of the pharmaceutically active ingredient in the osmotic pump controlled release formulation satisfies one or more of the following release properties:
  • the release degree at 4 hours is 4% to 30%;
  • the release at the 12-hour time point is 40% to 85%;
  • the release at 24 hours is greater than 90%.
  • the release behavior of the pharmaceutically active ingredient in the osmotic pump controlled release formulation satisfies one or more of the following release properties:
  • the release degree at 4 hours is 4% to 20%
  • the release at the 12-hour time point is 40% to 80%.
  • the release at 24 hours is greater than 90%.
  • the osmotic pump controlled-release preparation provided by this application can release drugs at a constant drug release rate within a certain time range.
  • the osmotic pump controlled-release preparation is in 900 mL of phosphate-citrate buffer medium of 1% sodium lauryl sulfate, 37°C, paddle method , at 100 rpm, the release at 4 hours, 12 hours, and 24 hours can reach 4% to 20%, 40% to 80%, and >90% respectively, which can avoid large fluctuations in blood concentration of ordinary oral preparations. , reduce the frequency of medication, and improve the safety, effectiveness and compliance of the medication. Please refer to Figure 3.
  • the osmotic pump controlled-release preparation is prepared in 900 mL of artificial intestinal juice without trypsin at 37°C, paddle method, 50 rpm, for 4 hours and 12 hours.
  • the release degree at 24 hours can reach 4% to 40%, 40% to 85%, and >90% respectively, which can avoid large fluctuations in blood concentration of ordinary oral preparations, reduce the number of medication doses, and improve the safety of the drug. , effectiveness and compliance. Please refer to Figure 6.
  • the osmotic pump controlled-release preparation is prepared in 500 mL of 0.1 mol/L hydrochloric acid solution at 37°C, paddle method, 50 rpm, for 4 hours and 12 hours.
  • the release degree at 24 hours can reach 4% ⁇ 20%, 40% ⁇ 80%, and > 90% respectively, which can avoid large fluctuations in blood concentration of ordinary oral preparations, reduce the frequency of medication, and improve the safety of the drug. , effectiveness and compliance.
  • the osmotic pump controlled-release preparation is prepared in 900 mL of 0.1 mol/L hydrochloric acid solution at 37°C, paddle method, 75 rpm, for 4 hours,
  • the release rate at 12 hours and 24 hours can reach 4% to 30%, 40% to 85%, and >90% respectively, which can avoid large fluctuations in blood concentration of ordinary oral preparations, reduce the number of doses, and improve the drug's potency.
  • Safety, effectiveness and compliance please refer to Figure 8.
  • the osmotic pump controlled-release preparation is prepared in 500 mL of 0.2% (w/v) sodium chloride in 0.1 mol/L hydrochloric acid solution at 37°C using the paddle method. , at 50 rpm, the release at 4 hours, 12 hours, and 24 hours can reach 4% to 30%, 40% to 85%, and >90% respectively, which can avoid large fluctuations in blood concentration of ordinary oral preparations. , reduce the frequency of medication, and improve the safety, effectiveness and compliance of the medication. Please refer to Figure 9.
  • an osmotic pump controlled release composition which is composed of each component 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. release preparations.
  • 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 application.
  • the preparation method includes the following steps in sequence:
  • S300 Cover the outer surface of the tablet core with a controlled release coating layer, and then punch holes in the controlled release coating layer to form a controlled release coating layer with drug release holes;
  • Step S100 includes sub-steps S110 and S120.
  • S110 prepare drug-containing layer particles according to each component of the drug-containing layer
  • S120 prepare booster layer particles according to each component of the booster layer. There is no order restriction between the two sub-steps S110 and S120.
  • a method for preparing an osmotic pump controlled-release preparation includes the following steps: 1 Prepare drug-containing layer particles, and prepare booster layer particles; 2 Press drug-containing layer particles and booster layer particles into Double-layer tablet core; 3 Coat the outer surface of the tablet core with a controlled-release coating layer; 4 Punch holes in the controlled-release coating layer to form a drug-release hole connecting the drug-containing layer and the outside; 5
  • a controlled-release coating layer is added to the outer surface of the tablet core.
  • the release coating layer is covered with a water-soluble coating film (such as a moisture-proof coating film).
  • a method for preparing an osmotic pump controlled-release preparation includes the following preparation steps according to the order of the preparation steps: (1) Preparation of drug-containing composition particles; (2) Preparation of booster layer particles; (3) ) Pressing of double-layer tablet core; (4) Controlled release coating; (5) Perforation of coated tablets; (6) Coating with water-soluble coating film (if any).
  • a method for preparing an osmotic pump controlled-release preparation including the following preparation steps:
  • Avoid light operation Mix the prescribed amount of medicine that has passed through a 60-mesh sieve with the excipients of the drug-containing layer, add it to the fluidized bed, spray 80% ethanol-water solution for granulation, stop granulating when the appropriate particle size is reached, dry, and pass through a 20-mesh sieve for granulation. , add magnesium stearate, mix well, and set aside.
  • auxiliary materials of the booster layer that have passed through a 60-mesh sieve in the recipe evenly, add them to the fluidized bed, and spray the aqueous solution for granulation.
  • stop granulating and dry pass the 20-mesh sieve into granules, and add stearic acid. Magnesium, mix well and set aside.
  • a controlled-release semipermeable membrane coating liquid prepare a controlled-release semipermeable membrane coating liquid; coat the double-layer tablet core that has passed the above inspection with a controlled-release semipermeable membrane coating liquid, and dry the coated product at 50°C. 12 hours to remove excess organic solvent and moisture.
  • coated tablets that have passed the above inspection, use a laser drilling machine or machinery to drill a drug release hole with a diameter of 0.6 to 1.0 mm on the surface of the drug-containing layer of the tablet.
  • Disperse the coating powder such as moisture-proof coating powder
  • a coating solution with a solid content of 5-15%.
  • the perforated tablets are placed in a high-efficiency coating pot and coated with the above-prepared coating liquid until the predetermined coating weight gain is reached; dried at 60°C for 2 hours to remove excess water to obtain an osmotic pump controlled release preparation. .
  • a booster layer composition which is composed of a penetration-promoting polymer, a water-insoluble swelling polymer, an osmotic pressure accelerator and pharmaceutical excipients 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 the first aspect of the application.
  • the penetration-enhancing polymer is a combination of alginate and hydroxyethyl cellulose.
  • Alginate is defined as previously stated.
  • the alginate is sodium alginate.
  • the push layer composition provided in this application is composed of a specific penetration-promoting polymer (optional a combination of alginate and hydroxyethyl cellulose, where the alginate is such as sodium alginate) and a suitable water-insoluble swelling polymer Materials (including at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone, further such as sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose At least one of the base celluloses, further such as sodium carboxymethyl starch and/or low-substituted hydroxypropyl cellulose, which can be sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, or A combination of sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose), an osmotic pressure accelerator and other boosting layer excipients (pharmaceutical excipient F2), forming a high-stre
  • the booster layer composition can be suitable for 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 Stable and controlled release of active ingredients is achieved in different dissolution media, and drug release is complete.
  • the osmotic pump controlled-release preparation prepared by using the unexpectedly discovered push layer composition also has the following beneficial effects: the excipients have good stability and are not easy to aggregate during the preparation process, and the active ingredients in the product The release is more stable and the release difference between tablets is small.
  • the application of the osmotic pump controlled-release preparation of the first aspect of the present application as an oral controlled-release preparation is provided.
  • the osmotic pump controlled release formulation is an oral controlled release tablet.
  • the specifications are 200-1000mg/tablet.
  • the weight of each tablet can also be selected from any one or two of the following ranges: 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, etc.
  • 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 is provided.
  • the active ingredient of the drug is nifedipine.
  • preventing and/or treating cardiovascular disease refers to at least one aspect of preventing cardiovascular disease and treating cardiovascular disease.
  • the cardiovascular disease includes at least one of hypertension and coronary heart disease chronic stable angina (exertional angina).
  • the cardiovascular disease is hypertension or coronary heart disease chronic stable angina.
  • a method for preventing cardiovascular disease includes administering to a subject a prophylactically effective amount of the osmotic pump controlled-release formulation described in the first aspect of the present application, or administering to a subject a preventive effective amount of the present invention. Apply for the osmotic pump controlled release composition described in the second aspect.
  • the cardiovascular disease includes at least one of hypertension, coronary heart disease and chronic stable angina.
  • a quality method for cardiovascular diseases includes 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 present invention.
  • the cardiovascular disease includes at least one of hypertension, coronary heart disease and chronic stable angina.
  • an osmotic pump controlled-release preparation for at least one of preventing and treating cardiovascular diseases is provided, and the osmotic pump controlled-release preparation is as defined in the first aspect of the present application.
  • an osmotic pump controlled-release composition for at least one of preventing and treating cardiovascular diseases is provided, and the osmotic pump controlled-release composition is as defined in the first aspect of the present application.
  • cardiovascular disease may be as defined in the sixth aspect of this application.
  • prevention of disease means preventing the occurrence or progression of a disease or condition.
  • treatment 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 or preventing its progression. Or alleviate to some extent.
  • drug includes any agent, compound, composition or mixture that provides at least one of physiological and pharmacological effects in vivo or in vitro, often providing a beneficial effect.
  • drug includes any agent, compound, composition or mixture that provides at least one of physiological and pharmacological effects in vivo or in vitro, often providing a beneficial effect.
  • the scope of the drug that produces physiological effects in the body or the scope of the pharmacological effects that it produces in the body. Each of them may independently have a systemic effect or only a local effect.
  • the "subject” is an animal, preferably a mammal, and further preferably a human.
  • Subjects include, but are not limited to, patients having at least one of the disease, disorder and related symptoms, or potential populations of these patients.
  • “Potential population of these patients” is the following group of people: although they do not have the disease, disease and related symptoms, they have not yet been identified as “patients", But there is a risk or possibility of developing a "patient”.
  • mammal mainly refers to warm-blooded vertebrate mammals, including but not limited to: cats, dogs (dogs), rabbits, bears, foxes, wolves, monkeys, deer, mice (such as rats, mice), pigs, cattle, sheep, horses, humans, etc. Primates are preferred, and humans are further preferred.
  • the subject is a human or a canine.
  • patient refers to an animal, which may preferably be a mammal, such as a human or a dog.
  • a “prophylactically effective amount” refers to an amount of a pharmaceutically active ingredient that will elicit a biological or medical response in an individual in response to the onset or progression of at least one of the diseases, conditions and associated symptoms, e.g. The amount of active pharmaceutical ingredient that brings at least one positive physiological or pharmacological effect to an individual.
  • a "therapeutically effective amount” refers to an amount of a pharmaceutically active ingredient that will elicit a biological or medical response in an individual for at least one of the diseases, conditions, and related symptoms, e.g., provide the individual with An amount of a pharmaceutical active ingredient that has at least one positive physiological and pharmacological effect, including but not limited to reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression or prevention of disease, etc.
  • the administration method of the preparations or compositions in the seventh, eighth, ninth, and tenth aspects of the present application can each independently be oral, and is not limited thereto.
  • the measurement parameters of raw material components are involved. Unless otherwise specified, there may be slight deviations within the range of weighing accuracy. Temperature and time parameters are involved, allowing for acceptable deviations due to instrument testing accuracy or operating accuracy.
  • Nifedipine a micronized product from Shaanxi Xiyue Pharmaceutical Co., Ltd.
  • Micropowder silica gel from Evonik Specialty Chemicals (Shanghai) Co., Ltd., pharmaceutical grade;
  • Low-grade hydroxypropyl cellulose was selected from Japan's Shin-Etsu Chemical Industry Co., Ltd., pharmaceutical grade;
  • Magnesium stearate Qufu Tianli Pharmaceutical Excipients Co., Ltd., pharmaceutical grade.
  • Tablet hardness tester Tianjin Tianda Tianfa Technology Co., Ltd., YD-20KZ;
  • Fluidized bed Chuangzhi Mechanical and Electrical Technology Development Co., Ltd., FLZB-0.5;
  • Avoid light operation Mix the prescribed amount of medicine that has passed through a 60-mesh sieve and the excipients of the drug-containing layer evenly, add it to the fluidized bed, spray 80% ethanol-water solution for granulation, stop granulating when the appropriate particle size is reached, dry, and pass through a 20-mesh sieve for granulation. , add magnesium stearate, mix well, and set aside.
  • auxiliary materials of the booster layer that have passed through a 60-mesh sieve in the recipe evenly, add them to the fluidized bed, and spray the aqueous solution for granulation.
  • stop granulating and dry pass the 20-mesh sieve into granules, and add stearic acid. Magnesium, mix well and set aside.
  • an isolation coat aqueous solution use the isolation coat coating solution for the double-layer tablet core that has passed the above inspection. After coating, the coated product is dried at 50°C for 12 hours to remove excess moisture.
  • a controlled-release semipermeable membrane coating liquid prepare a controlled-release semipermeable membrane coating liquid; coat the double-layer tablet core that has passed the above inspection with a controlled-release semipermeable membrane coating liquid, and dry the coated product at 50°C. 12 hours to remove excess organic solvent and moisture.
  • HPLC detection chromatography conditions are as follows: the chromatographic column uses an octadecyl-bonded silica gel column, the mobile phase is methanol:water (50:50), the flow rate is 1.0mL/min, and the detection wavelength is 235nm.
  • the 24h release of the controlled-release tablets of comparative prescription 5-comparative prescription 8 is lower than 90%. It can be seen that under a specific prescription composition, hydroxyethyl cellulose or seaweed alone is used. sodium phosphate, or replacing one of hydroxyethylcellulose or sodium alginate with conventional polymers, may result in a reduction in final release.
  • the combination of the booster layer of hydroxyethyl cellulose and sodium alginate helps to control the release of drugs in the drug-containing layer without an isolation coat, and can significantly improve the final release of tablets.
  • the release curves of each of the above prescription tablets are shown in Figures 3 and 4.
  • hydroxyethyl cellulose and sodium alginate forms a high-strength and high-toughness hydrogel, which helps to improve the mechanical properties of the booster layer composition, ensure the uniform release of active ingredients in the drug-containing layer, and improve the drug's effectiveness. Final release amount.
  • Prescription 11 Take the controlled-release tablet to be tested, and put the tablet into a small metal mesh basket according to the second method of dissolution and release determination in Appendix 0931 of the Chinese Pharmacopoeia 2020 Edition to avoid the presence of trypsin. 900mL of artificial intestinal fluid is used as the solvent, and the rotation speed is 50 rpm. Operate according to the law. Take 8mL of the solution at 4 hours, 8 hours, 12 hours, 16 hours and 24 hours respectively, and filter it with a 0.45 ⁇ m microporous filter membrane. Continue The filtrate is used as the release test solution, and 8 mL of the above solvent is immediately added to the operating container.
  • glipizide reference substance Take another 50 mg of the glipizide reference substance, weigh it accurately, put it in a 100 mL volumetric flask, add 20 mL of methanol, dissolve it with ultrasound, dilute it to the mark with methanol, shake well, and use it as a stock solution; take 1 mL of the stock solution and put it into a 100 mL volume. In the bottle, use artificial intestinal juice without trypsin as the solvent and dilute to the mark to prepare glipizide reference solution.
  • control solution Take the control solution and the test solution respectively, use spectrophotometry to measure the absorbance at a wavelength of 276nm, and calculate the release amount of each tablet at different times using the external standard method.
  • HPLC detection chromatography conditions are as follows: the chromatographic column adopts octadecylsilane bonded silica gel column; use acetonitrile-0.035M phosphate buffer (take 4.83g sodium dihydrogen phosphate, 5mL triethylamine, add water to 1000mL, adjust with phosphoric acid pH value to 2.2 ⁇ 0.05) (35:65 volume ratio) is the mobile phase; the detection wavelength is 220nm; the flow rate is 1.5mL/min; the injection volume is 10 ⁇ L.
  • Prescription 13 Take the controlled-release tablet to be tested, use the second method device for determination of dissolution and release in the fourth appendix 0931 of the Chinese Pharmacopoeia 2020 edition, put the tablet into a small metal mesh basket, and measure 0.1 mol/L 900mL of hydrochloric acid solution is used as the release medium. The rotation speed is 75 rpm. Operate according to the law. After 4 hours, 8 hours, 12 hours, 16 hours, and 24 hours, take 10mL of each solution, centrifuge (8000rpm, 15min), and take the supernatant. The solution is used as the release test solution, and the same volume of release medium is added at the same time.
  • Prescription 14 Take the controlled-release tablet to be measured, use the second method device for determination of dissolution and release in the fourth appendix 0931 of the Chinese Pharmacopoeia 2020 edition, put the tablet into a small metal mesh basket, and measure the dissolution rate with 0.2% (w /v) 500mL of sodium chloride hydrochloric acid solution (hydrochloric acid concentration is about 0.1mol/L) is used as the release medium, and the rotation speed is 50 rpm. Operate according to the law.
  • paliperidone reference substance In addition, take an appropriate amount of paliperidone reference substance, weigh it accurately, add methanol to dissolve and dilute it to make a solution containing 60 ⁇ g 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, and add 0.2 % sodium chloride (w/v, %) hydrochloric acid solution was made into a solution containing 12 ⁇ g of paliperidone per 1 mL, which was used as a reference solution.
  • the use of the booster layer composition described in this application can help improve the mechanical properties of the booster layer composition, and can form a high-strength and high-toughness hydrogel in an aqueous medium; the booster layer provided by this application
  • the composition can be suitable for controlled-release administration of a variety of active ingredients (including glipizide, oxybutynin hydrochloride, doxazosin mesylate, paliperidone, etc.) and can be uniformly distributed in different dissolution media. Achieves complete release of active ingredients.
  • nifedipine reference substance Take another 18 mg of nifedipine reference substance, weigh it accurately, put it in a 50 mL brown measuring bottle, add 30 mL of methanol to dissolve it, add water to dilute to the mark, shake well; accurately measure 5 mL, put it in a 50 mL brown measuring bottle, and use 1% ten Dilute sodium dialkyl sulfate in phosphate-citrate buffer to volume, shake well, and use it as a reference solution.
  • Comparative Prescription 2 uses a conventional combination of sodium alginate, carbomer and copovidone VA64. Without an isolation coat, there is incomplete release ( ⁇ 90%). It is speculated that it is released at the lower end of the intestine (the water content is relatively low). intestinal segment), absorption is relatively poor.
  • Avoid light operation Take the controlled-release tablet to be tested, put the tablet into a small metal mesh basket, and add 5%, 10%, 20%, and 40% (v/v) of the prepared buffer solution containing 1% sodium lauryl sulfate respectively. of absolute ethanol. After mixing evenly, use 900 mL as the dosage of 5%, 10%, 20%, and 40% ethanol to pour and examine the release medium. The rotation speed is 100 rpm. Operate in accordance with the law. After 2 hours, 4 hours, and 8 hours and 12 hours, take 8 mL of each solution, filter it with a 0.45 ⁇ m microporous filter membrane, and use it as the test solution; at the same time, add the release medium of the same temperature and volume.
  • nifedipine reference substance Take another 18 mg of nifedipine reference substance, weigh it accurately, put it in a 50 mL brown volumetric flask, add 30 mL of methanol to dissolve, add water to dilute to the mark, and shake well; accurately measure 5 mL, place it in a 50 mL brown volumetric flask, and dilute with release medium to the mark, shake well, and use it as a reference solution. Precisely measure 25 ⁇ L each of the reference solution and the test solution, and inject it into the high-performance liquid chromatograph, using an octadecyl-bonded silica gel column.
  • the preparation method is as follows: Take 6.8g of potassium dihydrogen phosphate, add 500mL of water to dissolve, and adjust the pH value to 6.8 with 0.1mol/L sodium hydroxide solution. Add 10g of Tween 80 to disperse and dissolve; take another 10g of trypsin, add an appropriate amount of water to dissolve, mix the two solutions, add water to dilute to 1000mL, and you have it.
  • Avoid light operation Take the controlled-release tablet to be tested, use 900mL of the above simulated intestinal juice as the release medium, and operate at a speed of 100 rpm. Operate according to the law. At 4 hours, 8 hours, 12 hours, 16 hours, and 24 hours, take 8 mL of each solution and use 0.45 ⁇ m Filtrate with a microporous membrane, and supplement the release medium with the same temperature and volume at the same time; centrifuge at 8000 rpm for 10 minutes, and remove the supernatant as the test solution.
  • nifedipine reference substance Take another 30 mg of nifedipine reference substance, weigh it accurately, put it in a 100 mL brown volumetric flask, add 50 mL of methanol to dissolve, add water to dilute to the mark, and shake well; accurately measure 5 mL, place it in a 50 mL brown volumetric flask, and dilute with release medium to the mark, shake well, and use it as a reference solution. Precisely measure 25 ⁇ L each of the reference solution and the test solution, and inject them into the high-performance liquid chromatograph, using 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 is 235nm, and the cumulative release amount of each tablet at different time points is calculated based on the peak area according to the external standard method.
  • the plasma was stored in a -80°C refrigerator and analyzed by LC-MS (liquid chromatography/ Mass spectrometry) was used to analyze blood drug concentration, draw drug-kinetic curves, and collect statistics on drug-kinetic parameters.
  • LC-MS liquid chromatography/ Mass spectrometry
  • the canine pharmacokinetic study results of Preparation Example Prescription 6 and Comparative Prescription 3 are shown in Table 7, Table 8, Table 9 and Figure 14.
  • the nifedipine controlled-release tablets of Prescription 6 are better in dogs than the Comparative Prescription 3 tablets. Individual differences in absorption are smaller.
  • the use of the booster layer composition of the present application helps to improve the mechanical properties of the booster layer composition.
  • the booster layer polymer can form a high-strength and high-toughness hydrogel, which is beneficial to achieving inter-chip replacement. Stable release, less drug residue in the tablet core, more complete drug release, and better in vivo release uniformity.
  • Prescription 6 has a higher C max and higher AUC after absorption in the body. This may be due to the fact that the booster layer composition of the present application can achieve more uniform and complete release. Conducive to the complete absorption of drugs in the body.
  • booster layer penetration enhancers such as sodium alginate, sodium carboxymethylcellulose, sodium chloride, etc.
  • osmotic pressure accelerators such as sodium alginate, sodium carboxymethylcellulose, sodium chloride, etc.
  • the booster layer is easily broken and lost due to the collision between tablets during the rolling coating process, resulting in coating failure or release differences between tablets.
  • the double-layer tablet core pressed by the drug-containing layer and booster layer particles of the different embodiments mentioned above was placed in a coating pot (Chuangzhi CHC-38), and the coating parameters (main engine speed 20 rpm, inlet air temperature) were adjusted. 30°C, spray pressure 0.05MPa), take samples after rolling for 5 minutes, 10 minutes, and 30 minutes, weigh, and calculate the friability (calculation formula: weight loss/original weight ⁇ 100%).
  • Tablet cores of prescription 4, prescription 5 and prescription 8 using hydroxyethyl cellulose As the dosage of hydroxyethyl cellulose increases, the friability after rolling in the coating pot is good. The friability after rolling for 30 minutes They are 0.4%, 0.2% and 0.1% respectively.
  • the addition of hydroxyethyl cellulose can also help to improve the friability of the tablet core compressed by the drug-containing layer and the booster layer, increase the quality stability of the double-layer tablet core, and reduce the coating During the process, the difference in core quality of the booster layer caused by the difference in friability between tablets can be improved to improve the defect of large release differences within the product batch.

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Abstract

一种渗透泵控释制剂，包括由内至外依次排列的如下结构：含药层和助推层的片芯，带释药孔的控释衣层，可选的水溶性包衣膜；其中，释药孔连通含药层和渗透泵控释制剂的外部；助推层则位于含药层远离释药孔的一侧；含药层包含药物活性成分，助推层包括促渗透聚合物，促渗透聚合物包含羟乙基纤维素和海藻酸盐。

Description

渗透泵控释制剂、渗透泵控释组合物、制备方法和应用
相关申请
本申请要求于2022年7月26日提交的、申请号为CN2022108875383、名称为“渗透泵控释制剂、渗透泵控释组合物、制备方法和应用”的中国专利申请的优先权，在此将其全文引入作为参考。
技术领域
本申请涉及药物制剂技术领域，特别涉及一种渗透泵控释制剂、渗透泵控释组合物、制备方法和应用。
背景技术
口服渗透泵制剂最早由美国ALZA公司于1970年研发，自1983年以来已有十多个产品上市。目前，渗透泵制剂主要用于半衰期短或需频繁给药、治疗窗窄的药物，比如治疗心血管疾病、心绞痛、高血压、哮喘等慢性疾病的药物。
传统的双层片芯的推-拉型渗透泵是带有释药孔的半透膜包衣片，其片芯由含药层和助推层组成，片芯中的含药层由药物、亲水聚合物载体和其它辅料组成，片芯中的助推层则由一种或多种缓释聚合物、渗透压促进剂和其它辅料组成。片芯外包有半透膜，并在半透膜片两边的片面上开设有释药孔，药物通过释药孔与外环境相连。双层推-拉型渗透泵的释药原理之一，是助推层中的聚合物遇水发生的“控制性”膨胀作用，在该膨胀作用下，含药层被推动至衣膜孔外，从而实现药物释放。因此，助推层中的聚合物既需要具有膨胀助推作用，也需要具有适当的膨胀控制作用，进而实现药物的控制性释放。故，助推层中的聚合物辅料的种类和用量，是双层渗透泵控释片中控制药物释放的关键要素。
双层渗透泵控释片的助推层中的聚合物主要采用两类功能性辅料。其中一类是可控制助推层溶胀速率的促渗透聚合物，该类聚合物一般为水溶性聚合物，吸水溶胀后可凝胶化，高粘度凝胶能够调节助推层的整体膨胀速率，控制药物释放，已知的促渗透聚合物包括高分子量的聚氧乙烯、卡波姆、羟丙基甲基纤维素、聚维酮、共聚维酮、羟丙基纤维素等。助推层中的另一类功能性辅料是遇水可快速膨胀的不溶性聚合物，这类不溶性聚合物遇水膨胀速率快，可作为助推层的药物释放动力，已知的水不溶性聚合物包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮等。
促渗透聚合物，是一类自身具有较强吸水膨胀作用的聚合物，有些聚合物能够通过单一聚合物成分实现控制释放多重功能。例如，国外已上市的推-拉型渗透泵产品Adalat GITS(拜新同)、Glucotrol XL(瑞易宁)等药物的助推层中采用了高粘度的聚氧乙烯作为主要促渗透聚合物辅料，实现药物的零级释放。专利文献CN103816131A记载的氟比洛芬双层控释片和专利文献CN103948558A记载的泊沙康唑双层控释片，也使用了聚氧乙烯作为助推层中的促渗透聚合物。然而，本申请的发明人发现，聚氧乙烯熔点低，其为主要辅料的片芯组合物时，由于热敏性强，在片芯的压制过程中，易因产热形成“卷边”，突出的卷边在控释包衣容易形成包衣脆弱点，导致衣膜在释放过程中发生破裂和药物突释，剂量倾泻风险加大。
专利文献CN101856337A记载了一种以海藻酸钠作为促渗透聚合物的渗透控释药物传递系统，其中，海藻酸钠作为促渗透聚合物，并与共聚维酮、羧甲基淀粉钠等其他聚合物组合使用，该制剂需要于控释衣膜内表面与片芯之间设置了一层隔离衣，降低片芯与控释衣膜之间的剪切力，才能实现相对较好的药物释放度。如果不加隔离衣，24小时时点的释放度仅83.4％。
专利文献CN100563638C和CN100563637C中记载的推拉式双层控释片采用卡波姆、羟丙甲纤维素、共聚维酮中的任一种或其组合作为助推层的主要的促渗透聚合物。其中，专利文献CN100563637C记载的硝苯地平控释制剂，以卡波姆作为促渗透聚合物。然而，由于口服药用级卡波姆细粉的静电强易自身团聚，易导致混粉和制粒过程的均一性较差，片剂均匀性控制难度大，甚至导致某些生产批次释放不稳定或释放不完全(24小时时点的释放度＜90％)。而不含卡波姆的其他配方，如以羟丙甲纤维素、共聚维酮或者二者的组合作为促渗透聚合物的方案，则存在助推动力不足，导致药物释放不完全的情况(24小时时点的释放度＜90％)。
基于此，有必要进一步开发新的渗透泵控释片制剂，以实现药物的均匀、完全释放。
发明内容
基于此，有必要提供一种渗透泵控释制剂，该渗透泵控释制剂配方简单，无需包被隔离衣膜即可以在16～24小时控制药物稳定释放，24小时的释放度可大于90％。进一步还提供用于制备该渗透泵控释制剂的渗透泵控释组合物及制备方法和应用。
在本申请的第一方面，提供一种渗透泵控释制剂，其包括由内至外依次排列的如下结构：
包括含药层和助推层构成的片芯；
带释药孔的控释衣层；和
可选的水溶性包衣膜(该水溶性包衣膜可以作为防潮衣膜和美学外衣中至少一种)。
其中，所述释药孔连通所述含药层和所述渗透泵控释制剂的外部；所述助推层位于所述含药层远离所述释药孔的一侧；
其中，所述含药层由药物活性成分、亲水性聚合物载体和药用辅料F1组成；其中，所述药用辅料F1为不同于所述亲水性聚合物载体的药用辅料；
所述助推层由促渗透聚合物、水不溶性膨胀聚合物、渗透压促进剂和药用辅料F2组成；其中，所述促渗透聚合物包含羟乙基纤维素和海藻酸盐；所述水不溶性膨胀聚合物包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的一种或多种；其中，所述药用辅料F2为不同于所述促渗透聚合物、所述水不溶性膨胀聚合物及所述渗透压促进剂的药用辅料。
在一些实施方式中，所述促渗透聚合物包含羟乙基纤维素和海藻酸钠，所述水不溶性膨胀聚合物为羧甲基淀粉盐、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的任一种或者其组合；或者，
所述促渗透聚合物为羟乙基纤维素和海藻酸钠，所述水不溶性膨胀聚合物包括羧甲基淀粉盐、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的至少一种；或者，
所述促渗透聚合物为羟乙基纤维素和海藻酸钠，所述水不溶性膨胀聚合物为羧甲基淀粉盐、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的任一种或者其组合。
在一些实施方式中，所述渗透泵控释制剂满足如下特征中的一项或多项：
基于所述含药层的总重量，药物活性成分占所述含药层重量的4％～33％，所述亲水性聚合物载体占所述含药层重量的40％～96％(可选为40％～95％，另可选为40％～94％，另可选为65％～96％，另可选为65％～94％，另可选为65％～85％)，所述药用辅料F1占所述含药层重量的0～2％；
基于所述助推层的总重量，所述促渗透聚合物占所述助推层重量的11％～66％(可选为12％～65％，另可选为20％～65％、另可选为11％～50％，另可选为20％～50％，另可选为20％～40％)，所述水不溶性膨胀聚合物占所述助推层重量的12％～71％(可选为13％～70％，进一步可选为15％～60％，更进一步可选为20％～50％，更进一步可选为20％～40％)，所述渗透压促进剂占所述助推层重量的10％～45％(可选为14％～42％，进一步可选为15％～40％)，所述药用辅料F2占所述助推层重量的0.5％～2.5％；
所述含药层和所述助推层的重量比值为0.5～2，可选为0.8～1.6，另可选为0.8～1.5，另可选为0.9～1.5；
所述带释药孔的控释衣层，增重为所述片芯重量的6％～25％，可选为6％～21％，另可选为8～25％，另可选为8％～15％，另可选为10％～20％。
在一些实施方式中，基于所述含药层的总重量，药物活性成分占所述含药层重量的4％～33％，所述亲水性聚合物载体占所述含药层重量的40％～96％(可选为40％～95％，另可选为40％～94％，另可选为65％～96％，另可选为65％～94％，另可选为65％～85％)，所述药用辅料F1占所述含药层重量的0～2％；
基于所述助推层的总重量，所述促渗透聚合物占所述助推层重量的11％～66％(可选为12％～65％，另可选为20％～65％、另可选为11％～50％，另可选为20％～50％，另可选为20％～40％)，所述水不溶性膨胀聚合物占所述助推层重量的12％～71％(可选为13％～70％，进一步可选为15％～60％，进一步可选为20％～50％，更进一步可选为20％～40％)，所述渗透压促进剂占所述助推层重量的10％～45％(可选为14％～42％，进一步可选为15％～40％)，所述药用辅料F2占所述助推层重量的0.5％～2.5％；
所述含药层和所述助推层的重量比值为0.5～2，可选为0.8～1.6，另可选为0.8～1.5，另可选为0.9～1.5；
所述带释药孔的控释衣层的增重为所述片芯重量的6％～25％，可选为6％～21％，另可选为8～25％，另可选为8％～15％，另可选为10％～20％。
在一些实施方式中，在所述片芯与所述控释衣层之间不包括隔离衣膜。
在一些实施方式中，所述渗透泵控释制剂满足如下特征中的一项或多项：
所述助推层中不包含聚氧乙烯；
所述助推层中不包含卡波姆；
所述促渗透聚合物中的海藻酸盐选自海藻酸钠、海藻酸钾和海藻酸铵中的一种或多种。
在一些实施方式中，所述渗透泵控释制剂满足如下特征中的一项或多项：
所述释药孔的数量为一个或多个，任一个所述释药孔连通所述含药层和所述渗透泵控释制剂 的外部；
所述释药孔的直径为0.6～1.0mm。
在一些实施方式中，所述含药层满足如下特征中的一项或多项：
所述亲水性聚合物载体为聚维酮、共聚维酮或者其组合；
所述药用辅料F1选自助渗剂、抗静电剂和润滑剂中的一种或多种。
在一些实施方式中，所述含药层满足如下特征中的一项或多项：
所述助渗剂选自氯化钠、氯化钾、山梨醇、木糖醇、葡萄糖和蔗糖中的一种或多种，可选为氯化钠；
所述抗静电剂包括微粉硅胶、硬脂酸和聚乙二醇中的一种或者多种，可选为微粉硅胶；
所述润滑剂选自硬脂酸镁、聚乙二醇、硬脂富马酸钠和滑石粉中的一种或多种。
在一些实施方式中，在所述助推层中，所述促渗透聚合物主要包含羟乙基纤维素和海藻酸盐；
可选地，所述羟乙基纤维素和所述海藻酸盐的重量之和在所述促渗透聚合物中的重量占比大于80％。
在一些实施方式中，所述助推层满足如下特征中的一项或多项：
所述羟乙基纤维素和所述海藻酸盐的重量比为1:(1～60)，可选为1:(1.5～40)，进一步可选为1:(1.5～25)，更进一步可选为1:(1.5～20)，更进一步可选为1:(1.5～16)；
所述羟乙基纤维素在所述助推层中的重量占比为0.4％～22％(可选为0.5～20％)。
在一些实施方式中，在所述助推层中，所述药用辅料F2选自润滑剂、着色剂和助流剂中的一种或多种。
在一些实施方式中，在所述助推层中，所述水不溶性膨胀性聚合物包括羧甲基淀粉钠和低取代羟丙基纤维素中的至少一种，还可选地包含交联羧甲基纤维素钠和交联聚维酮中的一种或多种。
在一些实施方式中，在所述助推层中，所述渗透压促进剂选自氯化钠、氯化钾、氯化镁、山梨醇、木糖醇、葡萄糖和蔗糖中的一种或多种，可选为氯化钠。
在一些实施方式中，所述带释药孔的控释衣层由半透性控释衣膜材料和可选的药用辅料F3组成；其中，所述药用辅料F3为增塑剂和致孔剂中的一种或多种。
在一些实施方式中，所述渗透泵控释制剂满足如下特征中的一项或多项：
所述半透性控释衣膜材料为醋酸纤维素或含有醋酸纤维素的预混包衣粉；
所述药用辅料F3选自聚乙二醇、邻苯二甲酸二乙酯、柠檬酸三乙酯、三醋酸甘油酯和癸二酸二丁酯中的一种或多种；
所述药用辅料F3相对于所述半透性控释衣膜材料和所述药用辅料F3的重量之和的重量比为0～20％，可选为1％～10％，另可选为1％～7.4％。
在一些实施方式中，所述水溶性包衣膜的增重为所述片芯和所述带释药孔的控释衣层的重量之和的8％～20％。
在一些实施方式中，所述药物活性成分选自硝苯地平、格列吡嗪、盐酸奥昔布宁、甲磺酸多沙唑嗪和帕利哌酮中的任一种。
在一些实施方式中，所述药物活性成分为硝苯地平。
在一些实施方式中，所述含药层和所述助推层构成双层片芯。
在一些实施方式中，将所述渗透泵控释制剂在37℃、100rpm条件下控制释放，所述渗透泵控释制剂中的药物活性成分的释放行为，满足如下的一个或多个释放性质：
于4h时点的释放度大于4％；
于12h时点的释放度大于40％；和
于24h时点的释放度大于90％；
可选地，释放介质为900mL的1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液、900mL的不含胰酶的人工肠液、500mL的0.1mol/L盐酸溶液、900mL的0.1mol/L盐酸溶液或500mL的0.2％(w/v)氯化钠的0.1mol/L盐酸溶液。
在本申请的第二方面，提供一种渗透泵控释组合物，其由本申请的第一方面所述渗透泵控释制剂的各组分组成，用于制备所述渗透泵控释制剂。
在本申请的第三方面，提供一种渗透泵控释制剂的制备方法，可用于制备本申请的第一方面所述渗透泵控释制剂，该制备方法依次包括如下步骤：
根据所述含药层的各组分制备含药层颗粒，根据所述助推层的各组分制备助推层颗粒；
将所述含药层颗粒以及所述助推层颗粒在模具中压制成所述的片芯；
在所述片芯的外表面包被控释衣层，然后在所述的控释衣层上打孔，形成所述带释药孔的控释衣层；
可选地，包被所述水溶性包衣膜。
在本申请的第四方面，提供一种助推层组合物，其由促渗透聚合物、水不溶性膨胀聚合物、渗透压促进剂和药用辅料F2组成；其中，
所述促渗透聚合物、所述水不溶性膨胀聚合物、所述渗透压促进剂和所述药用辅料F2的定义如本申请的第一方面中所定义；
可选地，所述促渗透聚合物为羟乙基纤维素和海藻酸盐的组合。
在本申请的第五方面，提供本申请的第一方面所述渗透泵控释制剂作为口服控释制剂的应用。
在本申请的第六方面，提供本申请的第一方面所述渗透泵控释制剂，或者本申请的第二方面所述渗透泵控释组合物，或者本申请的第四方面所述助推层组合物在制备预防和/或治疗心血管疾病的药物中的应用，其中，所述药物活性成分为硝苯地平，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种；
其中，“预防和/或治疗心血管疾病”指预防心血管疾病和治疗心血管疾病中至少一方面。
在本申请的第七方面，提供一种心血管疾病的预防方法，包括给予受试者预防有效量的本申请第一方面所述渗透泵控释制剂，或者给予受试者预防有效量的本申请第二方面所述渗透泵控释组合物；
可选地，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种。
在本申请的第八方面，提供一种心血管疾病的质量方法，包括给予受试者治疗有效量的本申请第一方面所述渗透泵控释制剂，或者给予受试者治疗有效量的本申请第二方面所述渗透泵控释组合物；
可选地，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种。
在本申请的第九方面，提供用于预防心血管疾病和治疗心血管疾病中至少一方面的渗透泵控释制剂，所述渗透泵控释制剂如本申请第一方面所定义。
在本申请的第十方面，提供用于预防心血管疾病和治疗心血管疾病中至少一方面的渗透泵控释组合物，所述渗透泵控释组合物如本申请第一方面所定义。
经过大量的研究和探索，本申请的发明人在研究助推层膨胀机制的过程中意外地发现：以海藻酸盐(如海藻酸钠)和羟乙基纤维素作为主要促渗透聚合性辅料，并与不溶性膨胀聚合物(羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮等中一种或多种)及渗透压促进剂等组合使用构建助推层组合物，再与含药层构成片芯，各组分相互配合，协同作用，由此制备的渗透泵控释制剂可实现在16～24小时内实现完全释放(最终释放量>90％)，而且可以无需设置隔离衣膜即可实现药物24小时的完全释放(释放度>90％)；此外，采用上述组合物制备助推层，在制备混合或压片过程中，皆无或基本无团聚现象，片剂混合均匀度良好，生产过程质量可控性好。发明人推测具有如下机理：基于海藻酸盐分子链与羟乙基纤维素分子链间相互作用，羟乙基纤维素与海藻酸盐配合使用，可形成新型兼具高强度与高韧性的三维网状水凝胶体系，改善助推层组合物的力学性能(包括良好的压缩性、拉伸性能)，形成的高强度水凝胶可协同推进本品含药层活性成分的匀速释放，提高药物的最终释放量，有助于药物实现完全释放。
另外，在本申请制备实施过程中发现，促渗透聚合物羟乙基纤维素的加入，还可改善助推层中各组分颗粒间的粘合作用，改善双层片芯的压片力，有助于减少包衣工序过程中片面的破损，进而改善渗透泵控释制剂的释放稳定性。
本申请所提供的助推层组合物，由特定的促渗透聚合物(可选为海藻酸盐和羟乙基纤维素的组合，其中的海藻酸盐如海藻酸钠)以及合适的水不溶性膨胀聚合物(如包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的至少一种，进一步如包括羧甲基淀粉钠和低取代羟丙基纤维素中的至少一种，更进一步如羧甲基淀粉钠、低取代羟丙基纤维素或二者的组合)、渗透压促进剂和其他助推层辅料(药用辅料F2)组成，所形成的高强度高韧性的水凝胶，有助于改善助推层组合物水凝胶力学性能，推动含药层药物和辅料，以受控的释药速率，经控释衣层的释药孔释放，而且可以保障含药层活性成分的匀速释放，提高药物的最终释放量(24小时时点释放度＞90％)，有助于药物实现完全释放。该助推层组合物可适用于多种活性成分，包括但不限于格列吡嗪、盐酸奥昔布宁、甲磺酸多沙唑嗪和帕利哌酮的制备和控释给药，均可在不同溶出介质中实现稳定控制释放，且释药完全。
与传统的渗透泵控释片相比，本申请提供的渗透泵控释制剂使用前述意外发现的助推层组合物，还具有如下有益效果：辅料稳定性良好，不易在制备过程中聚集，产品中活性成分的释放更稳定，片间释放度差异小。
附图说明
为了更清楚地说明本申请实施例中的技术方案、更完整地理解本申请及其有益效果，下面将 对实施例描述中所需要使用的附图作简单的介绍。显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对本领域技术人员来说，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。还需说明的是，附图均采用简化的形式绘制，仅用于方便、明晰地辅助说明本申请。附图所示的每一部件的各种尺寸是任意示出的，可能是精准的，也可能是未按实际比例绘制。比如，为了使图示更清晰，附图中有些地方适当夸大了部件的尺寸。如无特别说明，图中各个部件并非按比例绘制。本申请并没有限定每个部件的每种尺寸。
其中，在下面的描述中相同的附图标号表示相同部分。
图1为本申请一实施方式中的渗透泵控释制剂结构示意图，其中的A和B对应具有不同数量释药孔的示意图；
图2为本申请一实施方式中的渗透泵控释制剂结构示意图；
图3为制备实施例中处方1～处方10硝苯地平控释片于900mL介质中的平均累积释放曲线图；
图4制备实施例中的对比处方1～对比处方8硝苯地平控释片于900mL介质中的平均累积释放曲线图；
图5为制备实施例中处方1和对比处方2硝苯地平控释片的助推层切面显微观察图；其中，A是对比处方2片剂1的助推层切面图；B是对比处方2的片剂2的助推层切面图；C是处方1的片剂1的助推层切面图；D是处方1的片剂2的助推层切面图；
图6为制备实施例中处方11格列吡嗪控释片的释放曲线图；
图7为制备实施例中处方12盐酸奥昔布宁控释片的释放曲线图；
图8为制备实施例中处方13甲磺酸多沙唑嗪控释片的释放曲线图；
图9为制备实施例中处方14帕利哌酮控释片的释放曲线图；
图10为制备实施例处方1和对比处方2硝苯地平控释片于100mL介质中的释放曲线图；
图11为制备实施例中处方2硝苯地平控释片于5％、10％、20％和40％乙醇释放介质中的释放曲线图；
图12为制备实施例中对比处方2硝苯地平控释片于5％、10％、20％和40％乙醇释放介质中的释放曲线图；
图13为制备实施例中处方2和对比处方3的硝苯地平控释片于人工肠液中的释放曲线图；
图14为制备实施例中处方6和对比处方3的硝苯地平控释片犬口服给药后血药浓度-时间曲线图；
图15为不同处方的控释片在包衣锅内脆碎度考察结果。
附图标记说明：
图1中：1为含药层；2为助推层；3为控释衣层(控释衣膜)：4为释药孔；
图2中：1为含药层；2为助推层；3为控释衣层(控释衣膜)：4为释药孔；5为水溶性包衣膜。
具体实施方式
下面结合附图、实施方式和实施例，对本申请作进一步详细的说明。应理解，这些实施方式和实施例仅用于说明本申请而不用于限制本申请的范围，提供这些实施方式和实施例的目的是使对本申请公开内容理解更加透彻全面。还应理解，本申请可以以许多不同的形式来实现，并不限于本文所描述的实施方式和实施例，本领域技术人员可以在不违背本申请内涵的情况下作各种改动或修改，得到的等价形式同样落于本申请的保护范围。此外，在下文的描述中，给出了大量的细节以便提供对本申请更为充分地理解，应理解，本申请可以无需一个或多个这些细节而得以实施。
除非另有定义，本文所使用的所有的技术和科学术语与属于本申请的技术领域的技术人员通常理解的含义相同。本文中在本申请的说明书中所使用的术语只是为了描述实施方式和实施例的目的，不是旨在于限制本申请。
术语
除非另外说明或存在矛盾之处，本文中使用的术语或短语具有以下含义：
本文所使用的术语“和/或”、“或/和”、“及/或”的选择范围包括两个或两个以上相关所列项目中任一个项目，也包括相关所列项目的任意的和所有的组合，所述任意的和所有的组合包括任意的两个相关所列项目、任意的更多个相关所列项目、或者全部相关所列项目的组合。需要说明的是，当用至少两个选自“和/或”、“或/和”、“及/或”的连词组合连接至少三个项目时，应当理解，在本申请中，该技术方案毫无疑问地包括均用“逻辑与”连接的技术方案，还毫无疑问地包括均用“逻辑或”连接的技术方案。比如，“A及/或B”包括A、B和“A+B(也即A与 B的组合)”三种并列方案。又比如，“A，及/或，B，及/或，C，及/或，D”的技术方案，包括A、B、C、D中任一项(也即均用“逻辑或”连接的技术方案)，也包括A、B、C、D的任意的和所有的组合，也即包括A、B、C、D中任两项或任三项的组合，还包括A、B、C、D的四项组合(也即均用“逻辑与”连接的技术方案)。再如，“具有如下特征：A，及/或，B，及/或，C，及/或，D”的技术方案可以理解为“满足如下特征中的一项或多项：A、B、C和D”。
本申请中涉及“多个”、“多种”、“多次”、“多项”等，如无特别限定，指在数量上大于2或等于2。例如，“一种或多种”表示一种或大于等于两种，“一项或多项”表示一项或大于等于两项。
在本发明中，如无其他说明，“一种或多种”表示所列项目中的任一种或者所列项目的任意组合。类似地，“一个或多个”、“一项或多项”等以其他方式表示“一或多”的情形，如无其他说明，也做相同理解。
本文中所使用的“其组合”、“其任意组合”、“其任意组合方式”等中包括所列项目中任两个或任两个以上项目的所有合适的组合方式。
本文中，“合适的组合方式”、“合适的方式”、“任意合适的方式”等中所述“合适”，以能够实施本申请的技术方案、解决本申请的技术问题、实现本申请预期的技术效果为准。
本文中，“可选”、“更好”、“更佳”、“为宜”仅为描述效果更好的实施方式或实施例，应当理解，并不构成对本申请保护范围的限制。如果一个技术方案中出现多处“可选”，如无特别说明，且无矛盾之处或相互制约关系，则每项“可选”各自独立。在一个技术方案中，当“可选”与一个或多个“另可选”同时出现时，其中的任两个或任意更多个“可选”之间可以不结合，也可以结合形成不同的特征。
本申请中，“进一步”、“更进一步”、“特别”、“例如”、“如”、“示例”、“举例”等用于描述目的，表示内容上的差异，但并不应理解为对本申请保护范围的限制。在本发明中，如无其他说明，A(如B)，表示B为A中的一种非限制性示例，可以理解A不限于为B。
本申请中，“可选地”、“可选的”、“可选”，指可有可无，也即指选自“有”或“无”两种并列方案中的任一种。如果一个技术方案中出现多处“可选”，如无特别说明，且无矛盾之处或相互制约关系，则每项“可选”各自独立。例如，本申请中“可选地含有”、“可选地包含”等描述，表示“含有或不含有”。“可选的组分X”，表示组分X存在或不存在。还例如，“可选为”表示，可以“为”或“不为”。
本申请中，“第一方面”、“第二方面”、“第三方面”、“第四方面”等中，术语“第一”、“第二”、“第三”、“第四”等仅用于描述目的，不能理解为指示或暗示相对重要性或数量，也不能理解为隐含指明所指示的技术特征的重要性或数量。而且“第一”、“第二”、“第三”、“第四”等仅起到非穷举式的列举描述目的，应当理解并不构成对数量的封闭式限定。
本发明中所使用的术语“含有”、“包含”和“包括”是同义词，其是包容性或开放式的，不排除额外的、未被引述的要素。
本申请中，以开放式语言描述的技术特征或技术方案中，包括所列举内容组成的封闭式技术特征或技术方案，也包括包含所列举内容的开放式技术特征或技术方案。
本申请中，涉及到数值区间(也即数值范围)，如无特别说明，该数值区间内可选的数值的分布视为连续，且包括该数值区间的两个数值端点(即最小值及最大值)，以及这两个数值端点之间的每一个数值。如无特别说明，当数值区间仅仅指向该数值区间内的整数时，包括该数值范围的两个端点整数，以及两个端点之间的每一个整数，相当于直接列举了每一个整数。当提供多个数值范围描述特征或特性时，可以合并这些数值范围。换言之，除非另有指明，否则本文中所公开之数值范围应理解为包括其中所归入的任何及所有的子范围。该数值区间中的“数值”可以为任意的定量值，比如数字、百分比、比例等。“数值区间”允许广义地包括百分比区间，比例区间，比值区间等定量区间。
本申请中的温度参数，如无特别限定，既允许为恒温处理，也允许在一定温度区间内存在变动。应当理解的是，所述的恒温处理允许温度在仪器控制的精度范围内进行波动。允许在如±5℃、±4℃、±3℃、±2℃、±1℃的范围内波动。
本申请中，术语“室温”一般指4℃～35℃，较佳地指20℃±5℃。在本申请的一些实施例中，室温是指20℃～30℃。
在本申请中，涉及数据范围的单位，如果仅在右端点后带有单位，则表示左端点和右端点的单位是相同的。比如，3～5h表示左端点“3”和右端点“5”的单位都是h(小时)。
本申请中，如无特别限定，“约”表示在本数上下一定幅度的范围内，波动范围可因本数的类型和数值有所差异。该波动范围可以根据测试或计量方式的精度合理确认，例如，“约10mg” 可以表示选自10±0.4mg等。
在本申请中，涉及聚合物的“分子量”，如无其他说明，指重均分子量。
在本申请提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。除非和本申请的发明目的和/或技术方案相冲突，否则，本申请涉及的引用文献以全部内容、全部目的被引用。本申请中涉及引用文献时，相关技术特征、术语、名词、短语等在引用文献中的定义也一并被引用。本申请中涉及引用文献时，被引用的相关技术特征的举例、可选方式也可作为参考纳入本申请中，但以能够实施本申请为限。应当理解，当引用内容与本申请中的描述相冲突时，以本申请为准或者适应性地根据本申请的描述进行修正。
在本发明中，方法流程中涉及多个步骤的，除非本文中有明确的不同说明，这些步骤的执行并没有严格的顺序限制，其可以以描述以外的其他顺序执行。而且，任一个步骤可以包括多个子步骤或者多个阶段，这些子步骤或者阶段并不必然是在同一时刻执行完成，而是可以在不同的时刻执行，其执行顺序也不必然是依次进行，而是可以与其他步骤或者其他步骤的子步骤或者阶段的一部分轮流或者交替或者同时地执行。
在本申请中，术语“药用辅料”，应当理解，为符合现行药用辅料管理规范的药学上可接受的辅料。
在本申请中，“药学上可接受的”指在合理医学判断范围内适于施用患者且与合理益处/风险比相称的。
在本申请中，“患者”是指一种动物，可选为哺乳动物，更好的为人。术语“哺乳动物”主要是指温血脊椎类哺乳动物，包括但不限于：如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪、牛、羊、马和人类。
在本申请中，“药用辅料F1”是含药层中不同于亲水性聚合物载体的药用辅料；“药用辅料F2”是助推层中同于亲水性聚合物载体的药用辅料；“药用辅料F3”是带释药孔的控释衣层中的药用辅料，可以为增塑剂和/或致孔剂(即增塑剂和致孔剂中的一种或多种)。
在本申请中，如无其他说明，“于XX时点的释放度”，表示自开始释放(0h)，至XX时点内累计释放量占理论总释放量的百分比。比如，“于4h时点的释放度”可以表示自0～4h内的累计释放度，可通过百分比表示。
在本申请的第一方面，提供一种渗透泵控释制剂，其包括由内至外依次排列的如下结构：包括含药层和助推层的片芯，带释药孔的控释衣层，可选的水溶性包衣膜；其中，释药孔连通含药层和渗透泵控释制剂的外部；助推层位于含药层远离释药孔的一侧；含药层包含药物活性成分，助推层包括促渗透聚合物，促渗透聚合物包含羟乙基纤维素和海藻酸盐。配方简单，可以在无需包被隔离衣膜的情况下精确控制药物稳定释放时长及释放度，例如，可以于16～24小时控制药物稳定释放，24小时的释放度可大于90％。
在一些实施方式中，所述渗透泵控释制剂包括双层片芯结构，进一步地，所述双层片芯结构包括含药层和助推层。
在一些实施方式中，所述包括含药层和助推层的片芯为双层片芯结构。
在一些实施方式中，所述包括含药层和助推层的片芯由所述含药层和所述助推层构成。
在一些实施方式中，所述释药孔仅位于所述含药层的一侧，也即单侧。
在一些实施方式中，提供一种渗透泵控释制剂，其包括由内至外依次排列的如下结构：包括含药层和助推层的双层片芯，带释药孔的控释衣层，可选的水溶性包衣膜；其中，释药孔连通含药层和渗透泵控释制剂的外部，释药孔位于含药层的一侧；助推层位于含药层远离释药孔的一侧；含药层包含药物活性成分，助推层包括促渗透聚合物，促渗透聚合物包含羟乙基纤维素和海藻酸盐。配方简单，可以在无需包被隔离衣膜的情况下精确控制药物稳定释放时长及释放度，例如，可以于16～24小时控制药物稳定释放，24小时的释放度可大于90％。
在一些实施方式中，提供一种渗透泵控释制剂，其包括由内至外依次排列的如下结构：
包括含药层和助推层的片芯；
带释药孔的控释衣层；和
可选的水溶性包衣膜(该水溶性包衣膜可以作为防潮衣膜和/或美学外衣，也即可以作为防潮衣膜和美学外衣中的至少一种)；
其中，释药孔连通含药层和渗透泵控释制剂的外部；助推层位于含药层远离释药孔的一侧；
其中，含药层由药物活性成分、亲水性聚合物载体和药用辅料F1组成；其中，药用辅料F1为不同于亲水性聚合物载体的药用辅料；
助推层由促渗透聚合物、水不溶性膨胀聚合物、渗透压促进剂和药用辅料F2组成；其中，促渗透聚合物包含羟乙基纤维素和海藻酸盐；水不溶性膨胀聚合物包括羧甲基淀粉钠、低取代羟丙 基纤维素、交联羧甲基纤维素钠和交联聚维酮中的一种或多种；其中，药用辅料F2为不同于促渗透聚合物、水不溶性膨胀聚合物及渗透压促进剂的药用辅料。
应当理解，控释衣层中与助推层相邻的部分不设有释药孔。
该渗透泵控释制剂可以在16～24小时内控制药物稳定释放，24小时时点的释放度可大于90％，可在每日一次给药的频次下达到临床治疗效果，每次给药的疗效可持续24小时。
在一些实施方式中，渗透泵控释制剂的结构可参阅图1，其中的A和B分别对应不同数量释放孔的渗透泵控释片。图1中A和B所示的渗透泵控释制剂包括由内至外依次排列的如下结构：包括含药层1和助推层2的片芯；以及带释药孔4的控释衣层3；其中，释药孔4连通含药层1和渗透泵控释制剂的外部；助推层2位于含药层远离释药孔4的一侧。
在一些实施方式中，渗透泵控释制剂的结构可参阅图2，包括水溶性包衣膜的渗透泵控释片。图2所示的渗透泵控释制剂包括由内至外依次排列的如下结构：包括含药层1和助推层2的片芯，带释药孔4的控释衣层3，以及水溶性包衣膜5；其中，释药孔4连通含药层1和渗透泵控释制剂的外部；助推层2位于含药层远离释药孔4的一侧。
在一些实施方式中，基于含药层的总重量，硝苯地平占含药层重量的4％～33％，亲水性聚合物载体占含药层重量的40％～96％(可选为40％～95％，另可选为40％～94％，另可选为65％～96％，另可选为65％～94％，另可选为65％～85％)，药用辅料F1占含药层重量的0～2％；
基于助推层的总重量，促渗透聚合物占助推层重量的11％～66％(可选为12％～65％，另可选20％～65％、另可选为11％～50％，另可选为20％～50％，另可选为20％～40％)，水不溶性膨胀聚合物占助推层重量的12％～71％(可选为13％～70％，进一步可选为15％～60％，更进一步可选为20％～50％，更进一步可选为20％～40％)，渗透压促进剂占助推层重量的10％～45％(可选为14％～42％，进一步可选为15％～40％)，药用辅料F2占助推层重量的0.5％～2.5％；
含药层和助推层的重量比值为0.5～2，可选为0.8～1.6，另可选为0.8～1.5，另可选为0.9～1.5；
带释药孔的控释衣层的增重为片芯重量的6％～25％，可选为6％～21％，另可选为8～25％，另可选为8％～15％，另可选为10％～20％。
片芯
在一些实施方式中，片芯包括含药层和助推层。
在一些实施方式中，片芯由含药层和助推层构成，此时，片芯为双层片芯结构。
在一些实施方式中，含药层和助推层构成双层片芯，可参阅图1。
在一些实施方式中，含药层和助推层的重量比值为0.5～2。含药层和助推层的重量比值还可以选自如下任一种数值或任两种构成的区间：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等。含药层和助推层的重量比值还可以选自0.8～1.6、0.8～1.5、0.9～1.5、0.9～1.6等。
在一些实施方式中，促渗透聚合物包含羟乙基纤维素和海藻酸盐，水不溶性膨胀聚合物为羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的任一种或者其组合。
在一些实施方式中，促渗透聚合物为羟乙基纤维素和海藻酸盐，水不溶性膨胀聚合物包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的至少一种。
在一些实施方式中，促渗透聚合物为羟乙基纤维素和海藻酸盐，水不溶性膨胀聚合物为羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮的任一种或者其组合。
在一些实施方式中，促渗透聚合物包含羟乙基纤维素和海藻酸盐，水不溶性膨胀聚合物为羧甲基淀粉钠和低取代羟丙基纤维素中的任一种或者其组合。
在一些实施方式中，促渗透聚合物为羟乙基纤维素和海藻酸盐，水不溶性膨胀聚合物包括羧甲基淀粉钠和低取代羟丙基纤维素中的至少一种。
在一些实施方式中，促渗透聚合物为羟乙基纤维素和海藻酸盐，水不溶性膨胀聚合物为羧甲基淀粉钠和低取代羟丙基纤维素中的任一种或者其组合。
在一些实施方式中，促渗透聚合物中的海藻酸盐可以选自海藻酸钠、海藻酸钾和海藻酸铵中的一种或多种。
含药层
含药层是包括药物活性成分的结构层。
在一些实施方式中，含药层由药物活性成分、亲水性聚合物载体和药用辅料F1组成；进一步地，药用辅料F1为不同于亲水性聚合物载体的药用辅料。
在一些实施方式中，基于含药层的总重量，药物活性成分占含药层重量的4％～33％，亲水性聚合物载体占含药层重量的40％～96％(可选为40％～95％，另可选为40％～94％，另可选为65％～96％，另可选为65％～94％，另可选为65％～85％)，药用辅料F1占含药层重量的0～2％。
在一些实施方式中，基于含药层的总重量，药物活性成分占含药层重量的4％～33％，还可以选自如下任一种百分数或任两种构成的区间：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％等，还可以选自4％～30％、4％～25％、4％～20％、5％～30％、5％～25％、5％～20％、7％～30％、7％～25％、7％～20％、8％～30％、8％～25％、8％～20％等。
亲水性聚合物载体在含药层中的用量取决于片芯的组分和所要求的药物释放特性。在一些实施方式中，基于含药层的总重量，亲水性聚合物载体占含药层重量的40％～96％，还可以选自如下任一种百分数或任两种构成的区间：65％、66％、67％、68％、69％、70％、72％、74％、75％、76％、78％、80％、82％、84％、85％、86％、88％、90％、91％、92％、93％、94％、95％等，还可以选自40％～95％、40％～94％、65％～96％、65％～94％、65％～85％、65％～95％、65％～90％、65％～80％、70％～96％、70％～95％、70％～94％、70％～90％、75％～96％、75％～95％、75％～94％、75％～90％、75％～80％等。
在一些实施方式中，基于含药层的总重量，药用辅料F1占含药层重量的0～2％，还可以选自如下任一种百分数或任两种构成的区间：0.3％、0.33％、0.35％、0.4％、0.45％、0.5％、0.55％、0.6％、0.65％、0.7％、.75％、.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％等，还可以选自0.2％～2％、0.3％～2％、0.33％～2％、0.3％～1.6％、0.3％～1％、0.4％～1％、0.3％～0.9％、0.4％～0.9％、0.3％～0.8％、0.4％～0.8％等。
在一些实施方式中，药物活性成分选自硝苯地平、格列吡嗪、盐酸奥昔布宁、甲磺酸多沙唑嗪和帕利哌酮中的任一种。
在一些实施方式中，药物活性成分为硝苯地平。
在一些实施方式中，在含药层中，亲水性聚合物载体可以包括但不限于聚维酮、共聚维酮或者其组合。在一些实施方式中，在含药层中，亲水性聚合物载体为聚维酮、共聚维酮或者其组合。
在一些实施方式中，在含药层中，亲水性聚合物载体可以包括但不限于聚维酮K90、共聚维酮VA64或者其组合。在一些实施方式中，在含药层中，亲水性聚合物载体为聚维酮K90、共聚维酮VA64或者其组合。在一些实施方式中，在含药层中，亲水性聚合物载体为共聚维酮VA64和聚维酮K90的组合。
含药层还可以包含本领域中可用的其他含药层辅料(记为药用辅料F1)。在本申请中，“药用辅料F1”是含药层中不同于亲水性聚合物载体的药用辅料。在本申请中，药用辅料F1可以非限制性地包括助渗剂、抗静电剂、润滑剂中的一种或者多种。
在一些实施方式中，药用辅料F1选自助渗剂、抗静电剂和润滑剂中的一种或多种。
在一些实施方式中，在含药层中，助渗剂选自氯化钠、氯化钾、山梨醇、木糖醇、葡萄糖和蔗糖中的一种或多种，进一步可以为氯化钠。
在一些实施方式中，在含药层中，抗静电剂包括微粉硅胶、硬脂酸和聚乙二醇中的一种或者多种，进一步可以为微粉硅胶。
在一些实施方式中，在含药层中，润滑剂选自硬脂酸镁、聚乙二醇、硬脂富马酸钠和滑石粉中的一种或多种。在一些实施方式中，在含药层中，润滑剂选自硬脂酸镁、聚乙二醇和硬脂富马酸钠中的一种或多种。
助推层
助推层，作为具有自身膨胀和推动效果的高分子缓释材料层，能够起到助推并调节释放速率的作用。本申请的助推层中通常包含一种或多种缓释聚合物、渗透压促进剂和其他助推层辅料。助推层中的缓释聚合物是渗透泵控释制剂的重要组成部分，在本申请中，通常包含促渗透聚合物和不溶性膨胀聚合物。
在一些实施方式中，助推层由促渗透聚合物、水不溶性膨胀聚合物、渗透压促进剂和药用辅料F2组成；进一步地，促渗透聚合物包含羟乙基纤维素和海藻酸盐；更进一步地，水不溶性膨胀聚合物包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的一种或多种；更进一步地，药用辅料F2为不同于促渗透聚合物、水不溶性膨胀聚合物及渗透压促进剂的药用辅料。
本申请助推层中的促渗透聚合物是实现助推层控制性膨胀的关键组成之一。传统技术中，促渗透聚合物通常包含卡波姆、聚氧乙烯、聚维酮、共聚维酮、羟丙甲纤维素、羟丙基纤维素或其组合。卡波姆和聚氧乙烯是目前市售渗透泵控释制剂助推层中最常用的促渗透聚合物。然而，本申请的发明人发现，聚氧乙烯由于其熔点低，高速压片生产过程中易因产热而产生“卷边”现象，这种边缘凸起的“卷边”易导致包衣后存在衣膜脆弱点，有可能导致药物突释和安全性风险；本申请的发明人还发现，卡波姆由于静电作用强，导致其粉末本身易团聚、制粒过程易成团、不易 与其他辅料混匀，生产过程中片剂均匀度的控制难度大，终产品释放度的稳定性存在一些问题。本申请的发明人经实验探索发现，如果采用上述的促渗透聚合物与不溶性膨胀聚合物组合使用，制粒和压片过程生产工艺的弊端多，对生产的要求较高，混合不均匀的产品易导致释放不完全的情况(如最终释放量<90％)；或者需要通过增加隔离衣膜改善释放，增加了制备工序、生产的周期以及生产成本。
经过大量的研究和探索，本申请的发明人在研究助推层膨胀机制的过程中意外地发现：以海藻酸盐(如海藻酸钠)和羟乙基纤维素作为主要促渗透聚合性辅料，并与不溶性膨胀聚合物(羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮等中一种或多种)及渗透压促进剂等组合使用构建助推层组合物，再与含药层构成片芯，各组分相互配合，协同作用，由此制备的渗透泵控释制剂可实现在16～24小时内实现完全释放(最终释放量>90％)，而且可以无需设置隔离衣膜即可实现药物24小时的完全释放(释放度>90％)；此外，采用上述组合物制备助推层，在制备混合或压片过程中，皆无或基本无团聚现象，片剂混合均匀度良好，生产过程质量可控性好。
在一些实施方式中，基于助推层的总重量，促渗透聚合物占助推层重量的11％～66％(可选为12％～65％，另可选为20％～65％、另可选为11％～50％，另可选为20％～50％，另可选为20％～40％)，水不溶性膨胀聚合物占助推层重量的12％～71％(可选为13％～70％，进一步可选为15％～60％，更进一步可选为20％～50％，更进一步可选为20％～40％)，渗透压促进剂占助推层重量的10％～45％(可选为14％～42％，进一步可选为15％～40％)，药用辅料F2占助推层重量的0.5％～2.5％。
在一些实施方式中，基于助推层的总重量，促渗透聚合物占助推层重量的11％～66％，还可以选自如下任一种百分数或任两种构成的区间：12％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％等，还可以选自11％～50％、11％～40％、12％～65％、20％～65％、11％～50％、20％～50％、20％～40％等中的合适范围。
在一些实施方式中，在助推层中，促渗透聚合物主要包含羟乙基纤维素和海藻酸盐。所述“主要包含”指重量占比满足大于80％。也即，在助推层中，羟乙基纤维素和海藻酸盐(如海藻酸钠)的重量之和在促渗透聚合物中的重量占比大于80％。在一些实施例中，羟乙基纤维素和海藻酸盐(如海藻酸钠)的重量之和在促渗透聚合物中的重量占比还可以大于85％、大于90％、大于92％、大于94％、大于95％、大于96％、大于97％、大于98％、大于99％、等于100％等。
在一些实施方式中，促渗透聚合物中的海藻酸盐可以选自海藻酸钠、海藻酸钾和海藻酸铵中的一种或多种。
本申请的发明人推测机理如下：基于海藻酸盐(如海藻酸钠)分子链与羟乙基纤维素大分子链间相互作用，羟乙基纤维素与海藻酸盐(如海藻酸钠)配合使用可形成新型兼具高强度与高韧性的三维网状水凝胶体系，改善助推层组合物的力学性能(包括良好的压缩性、拉伸性能)，形成的高强度水凝胶可协同推进本品含药层活性成分的匀速释放，提高药物的最终释放量，有助于药物实现完全释放。
在一些实施方式中，在助推层中，促渗透聚合物由羟乙基纤维素和海藻酸盐组成。可用于本申请的海藻酸盐的粘度范围可选自但不限于20cps至1000cps，例如如下任一种粘度值或任两种粘度值构成的区间：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等。可用于本申请的海藻酸盐的粘度可选自下述范围中的合适范围：100cps～1000cps、100cps～800cps、100cps～700cps、140cps～650cps、140cps～600cps、143cps～600cps等。
在一些实施方式中，促渗透聚合物中的海藻酸盐为海藻酸钠。
在一些实施方式中，在助推层中，促渗透聚合物由羟乙基纤维素和海藻酸钠组成。
本申请所用的海藻酸盐(如海藻酸钠)是海藻酸与海水中的矿物质生成的天然产物，主要来源为褐藻中的海带或巨藻等，是由甘露糖醛酸(M)和古洛糖醛酸(G)组成的混聚多糖结构。海藻酸盐，水溶后，遇钙离子可迅速发生离子交换，生成凝胶，其凝胶具有热不可逆性。高G型海藻酸盐生成的凝胶硬度大但易碎；高M型海藻酸盐生成的凝胶则相反，柔韧性好但硬度小。调整两种比例可生产不同强度的凝胶。
本申请所使用的海藻酸钠，可应用于食品、药品中，安全性良好。可用于本申请的海藻酸钠的粘度范围可选自但不限于20cps至1000cps，例如如下任一种粘度值或任两种粘度值构成的区间：20cps、50cps、60cps、70cps、75cps、80cps、90cps、100cps、110cps、120cps、130cps、140cps、143cps、145cps、150cps、200cps、250cps、300cps、400cps、500cps、600cps、700cps、800cps、900cps、1000cps等。可用于本申请的海藻酸钠的粘度可选自下述范围中的合适范 围：100cps～1000cps、100cps～800cps、100cps～700cps、140cps～650cps、140cps～600cps、143cps～600cps等。本申请助推层中的海藻酸钠遇水缓慢溶胀为高粘的凝胶状，有助于控制不溶性聚合物的溶胀速率，实现均匀释放。
本申请所使用的海藻酸钾，是一种乳白色至浅黄色粉末或颗粒，具有良好的亲水性、流动性、增稠性、凝胶性，相同条件下其强度优于海藻酸钠，作为亲水性胶体，易溶于水形成粘稠溶液。本申请所使用的海藻酸钾可用于食品、保健品和药品中的一个或多个方面。本申请中使用的海藻酸钾的粘度范围可选自但不限于20cps至1000cps，例如如下任一种粘度值或任两种粘度值构成的区间：20cps、50cps、60cps、70cps、75cps、80cps、90cps、100cps、110cps、120cps、130cps、140cps、143cps、145cps、150cps、200cps、250cps、300cps、400cps、500cps、600cps、700cps、800cps、900cps、1000cps等。可用于本申请的海藻酸钾的粘度可选自下述范围中的合适范围：100cps～1000cps、100cps～800cps、100cps～700cps、140cps～650cps、140cps～600cps、143cps～600cps等。
本申请所使用的海藻酸铵，是一种浅黄色至褐色无定型粉末或颗粒，具有良好的亲水性、增稠性、凝胶性，作为亲水性胶体，易溶于水形成粘稠溶液。本品所使用的海藻酸钾可用于食品、保健品和药品中的一个或多个方面。可用于本申请的海藻酸铵的粘度范围可选自但不限于20cps至800cps，例如如下任一种粘度值或任两种粘度值构成的区间：20cps、50cps、60cps、70cps、75cps、80cps、90cps、100cps、110cps、120cps、130cps、140cps、143cps、145cps、150cps、200cps、250cps、300cps、400cps、500cps、600cps、700cps、800cps等。可用于本申请的海藻酸铵的粘度可选自下述范围中的合适范围：100cps～800cps、100cps～700cps、140cps～650cps、140cps～600cps、143cps～600cps等。
本申请所用的羟乙基纤维素，是一种非离子型水溶性聚合物材料，能够吸收水分并快速溶胀的高分子聚合物，羟乙基纤维素遇水快速凝胶化。通常羟乙基纤维素在药物制剂中可作为片剂粘合剂、骨架材料和膜包衣材料等使用，但尚未有将羟乙基纤维素用于助推层促渗透聚合物的相关研究。本申请发明人偶然地将羟乙基纤维素用于助推层，获得了令人意外的良好效果。
在一些实施方式中，在助推层中，羟乙基纤维素和海藻酸盐(如海藻酸钠)的重量比为1:(1～60)，进一步可以为1:(1.5～40)，更进一步可以为1:(1.5～25)，更进一步可以为1:(1.5～20)，更进一步可以为1:(1.5～16)。在助推层中，羟乙基纤维素和海藻酸盐(如海藻酸钠)的重量比还可以选自如下任一种或任两种构成的区间：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等。
在一些实施方式中，羟乙基纤维素在助推层中的重量占比为0.4％～22％，进一步可以为0.5～20％，还可以选自如下任一种百分数或任两种构成的区间：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％等，羟乙基纤维素在助推层中的重量占比还可以选自下述范围中的任一合适范围：1％～22％、1％～20％、2％～22％、2％～20％、2.5％～22％、2.5％～20％、4％～22％、4％～20％、5％～22％、5％～20％、0.5％～15％、1％～15％、2％～15％、2.5％～15％、4％～15％、5％～15％、0.5％～10％、1％～10％、2％～10％、2.5％～10％、4％～10％、5％～10％等。
在一些实施方式中，所述助推层满足如下特征中的一项或多项：
在助推层中，羟乙基纤维素和海藻酸盐(如海藻酸钠)的重量比为1:(1～60)，进一步可以为1:(1.5～40)，更进一步可以为1:(1.5～25)，更进一步可以为1:(1.5～20)，更进一步可以为1:(1.5～16)，还可参考前述重量比中合适的范围或取值；
在助推层中，羟乙基纤维素在助推层中的重量占比为0.4％～22％(进一步可以为0.5～20％)，还可参考前述重量占比中的合适取值或范围。
在本申请的一个实施方式中，海藻酸盐(如海藻酸钠)和羟乙基纤维素的渗透聚合物组合提供促渗透聚合物，在无需采用隔离衣膜的情况下，实现了24小时内90％以上的释放；在另一个实施例中(如制备实施例处方2和实验实施例4)，采用本申请中的海藻酸盐(进一步可以为海藻酸钠)和羟乙基纤维素的渗透聚合物组合制备的控释片，相较于羟丙甲纤维素K15M和/或共聚维酮(其中一者或者二者组合)，本申请所提供的技术方案中药物的最终释放量更完全，如制备实施例处方2片剂在24小时时点的释放度为102.7％，而制备实施例比对处方1片剂(羟丙甲纤维素K15M和共聚维酮的组合)的24小时释放度仅为86.7％。
在本申请中，羟乙基纤维素还可增加片剂各辅料颗粒间的粘合，羟乙基纤维素的加入使制备的渗透泵控释制剂(如双层片剂)具有良好的可压性，有利于实现高速压片和提高生产效率。
本申请助推层中的不溶性膨胀聚合物遇水可迅速膨胀，起到药物释放的助推作用。
在一些实施方式中，基于助推层的总重量，水不溶性膨胀聚合物占助推层重量的12％～71％， 还可以选自如下任一种百分数或任两种构成的区间：13％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％等，还可以选自12％～60％、12％～50％、12％～40％、13％～70％、13％～60％、13％～50％、13％～40％、15％～70％、15％～60％、15％～50％、15％～40％、20％～70％、20％～60％、20％～50％、20％～40％等。
在一些实施方式中，水不溶性膨胀聚合物包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的一种或多种。
在一些实施方式中，水不溶性膨胀聚合物为羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的任一种或者其组合(combination thereof)；“其组合”表示前述所列举水不溶性膨胀聚合物的任意合适的组合。
在一些实施方式中，水不溶性膨胀聚合物包括羧甲基淀粉钠和低取代羟丙基纤维素中的至少一种。进一步地，水不溶性膨胀聚合物还可选地包含交联羧甲基纤维素钠、交联聚维酮中的一种或多种。
在一些实施方式中，水不溶性膨胀聚合物包括羧甲基淀粉钠和低取代羟丙基纤维素。
在一些实施方式中，水不溶性膨胀聚合物为羧甲基淀粉钠和低取代羟丙基纤维素的组合。
在本申请中，“低取代羟丙基纤维素”可以由碱性纤维素与环氧丙烷，在高温高压下反应制得。羟丙基取代率可以为5％～16％，进一步如7％～16％。
在本申请的助推层中，含有渗透压促进剂。渗透压促进剂(如氯化钠等无机盐类渗透压促进剂)可能影响部分高分子材料的黏度，增加溶液的极性，压缩大分子双电层，使大分子链变得卷曲，导致黏度降低。而本申请中所使用的羟乙基纤维素的粘度，不受氯化钠含量的影响，抗盐性良好，可保证羟乙基纤维素在胃肠道吸水后，形成稳定凝胶体系，可实现药物的平稳释放。
在一些实施方式中，基于助推层的总重量，渗透压促进剂占助推层重量的10％～45％，进一步可以为14％～42％，更进一步可以为15％～40％，更进一步可以为15％～35％，更进一步可以为15％～30％。还可以选自如下任一种百分数或任两种构成的区间：15％、16％、18％、20％、25％、30％、35％、36％、38％、40％、41％等。
在一些实施方式中，在助推层中，渗透压促进剂为无机盐类渗透压促进剂，进一步可以为氯化钠。
在一些实施方式中，在助推层中，渗透压促进剂选自氯化钠、氯化钾、氯化镁、山梨醇、木糖醇、葡萄糖和蔗糖中的一种或多种，进一步可以为氯化钠。
在一些实施方式中，在助推层中，渗透压促进剂为氯化钠。氯化钠作为渗透压促进剂，理化性质稳定，具有良好的水溶性和良好的生物安全性。
在本申请中，助推层还可以包含本领域中可用的其他助推层辅料(记为药用辅料F2)。在本申请中，“药用辅料F2”是助推层中同于亲水性聚合物载体的药用辅料。在本申请中，药用辅料F2可以非限制性地包括润滑剂、着色剂等中的一种或者多种。
在一些实施方式中，在助推层中，药用辅料F2选自润滑剂、着色剂和助流剂中的一种或多种。
在一些实施方式中，基于助推层的总重量，药用辅料F2占助推层重量的0.5％～2.5％，进一步可以为0.5％～2％，更进一步如0.5％～1.5％。还可以选自如下任一种百分数或任两种构成的区间：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％等。
润滑剂的加入可改善本品含药层、助推层颗粒在高速压片过程中颗粒的流动性，改善药物制剂的含量及含量均匀度。助推层中的润滑剂可以选自但不限于硬脂酸、硬脂酸镁、硬脂富马酸钠、滑石粉、石蜡等中的一种或多种。
着色剂的使用可使药物的含药层和助推层易于区分，颜色的选择不影响本申请的实际用途及效果。助推层中的着色剂可以选自但不限于氧化铁红、氧化铁黄、氧化铁紫、氧化铁黑等中的一种或多种。
助流剂的使用，主要提高粉末或颗粒的流动性，利于压片工艺的稳定控制，助推层中的助流剂的选择范围包括但不限于微粉硅胶。
在一些实施方式中，在片芯与控释衣层之间不包括隔离衣膜。在一些实施方式中，在含药层和助推层之间不包括隔离衣膜。本申请提供的渗透泵控释制剂可以在不设置隔离衣膜的情况下实现较高的药物释放率(24小时时点释放超过90％)。
在一些实施方式中，助推层中不包含聚氧乙烯。可以克服传统助推层中聚氧乙烯的热敏性弊端。
在一些实施方式中，助推层中不包含卡波姆。可以避免混合、制粒不均一等带来片间释放不稳定等缺陷。
在本申请中，可以利用模具将含药层的各组分和助推层的各组分压制成片芯，如双层片芯结构。
带释药孔的控释衣层
在本申请中，控释衣层，也称作控释衣膜，是渗透泵控释组合物的关键组成部分，控释衣膜的存在可以使水分渗透通过，而助渗剂、渗透聚合物则无法通过，从而保证片芯内部相对独立的微环境。
在一些实施方式中，带释药孔的控释衣层的增重为片芯重量的6％～25％，可选为6％～21％，另可选为8～25％，另可选为8％～15％，另可选为10％～20％。还可以选自如下任一种百分数或任两种构成的区间：6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％等。
在一些实施方式中，带释药孔的控释衣层主要包括醋酸纤维素或含有醋酸纤维素的预混包衣粉(如欧巴代CA)，但不限于这些。
在一些实施方式中，带释药孔的控释衣层由半透性控释衣膜材料和可选的控释衣层辅料(记为药用辅料F3)组成；进一步地，药用辅料F3可以为增塑剂和/或致孔剂，药用辅料F3可以为增塑剂，也可以为致孔剂，还可以为增塑剂和致孔剂的组合。
在一些实施方式中，半透性控释衣膜材料为醋酸纤维素或含有醋酸纤维素的预混包衣粉。
在本申请的控释衣层中，致孔剂和/或增塑剂可以增加控释衣膜材料的水分通透性。
在一些实施方式中，基于控释衣膜的总重，药用辅料F3为增塑剂和/或致孔剂(也即增塑剂和致孔剂中的一种或二者组合)，且药用辅料F3在干燥衣膜中的重量占比为0～20％，进一步可以为1～10％，更进一步可以为1％～7.4％，更进一步可以为1～7％。还可以选自如下任一种百分数或任两种构成的区间：0.2％、0.4％、0.5％、0.6％、0.8％、.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％等，还可以选自0.5％～20％、0.5％～10％、0.5％～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％等。
在本申请中，控释衣膜的“干燥衣膜”指将控释衣膜材料和F3辅料溶于溶剂，经包衣工艺，包被至片芯后，再经干燥工艺除尽溶剂后所形成的衣膜。控释衣膜的“干燥衣膜”的主要成分是半透性控释衣材料和F3辅料组成。
在一些实施方式中，控释衣膜的干燥衣膜由半透性控释衣膜材料和药用辅料F3组成。此时，药用辅料F3相对于半透性控释衣膜材料和药用辅料F3的重量之和的重量比可以为0～20％，进一步可以为1％～10％，更进一步可以为1％～7.4％，更进一步可以为1％～7％。还可以选自前述任意合适的药用辅料F3在干燥衣膜中的重量占比。
在一些实施方式中，控释衣层中使用的致孔剂可以选自但不限于甘油、聚维酮、共聚维酮、丙二醇、聚乙二醇等。
本申请的控释衣层中使用的增塑剂可使控释衣膜具有更加良好的柔韧性和伸展性。
在一些实施方式中，药用辅料F3选自聚乙二醇、邻苯二甲酸二乙酯、柠檬酸三乙酯、三醋酸甘油酯、癸二酸二丁酯等中的一种或多种。
在一些实施方式中，在制备带释药孔的控释衣层时，适用于本申请的控释衣层的溶剂可以选自但不限于丙酮、水、乙醇、甲醇、异丙醇和二氯甲烷中的一种或多种。
在本申请中，控释衣膜可以采用高效包衣锅，通过喷涂的方式进行干燥后包裹于片芯上。
在一些实施方式中，控释衣层中带有至少一个通道(可记为释药孔)连接含药层和外部，使含药层药物能够释放出。在一些实施例中，可通过机械钻孔或者激光打孔的方式制备释药孔。
在一些实施方式中，释药孔的数量为一个或多个，进一步地，任一个释药孔连通含药层和渗透泵控释制剂的外部。
在一些实施方式中，任一个释药孔的直径为0.6～1.0mm。非限制性示例如0.6mm、0.7mm、0.8mm、0.9mm、1.0mm等。
可选的包衣膜
如无其他说明，本申请中的该包衣膜为水溶性包衣膜。
在本申请中，该水溶性包衣膜为可选结构，可以作为防潮衣膜和/或美学外衣，可以作为防潮衣膜，也可以作为美学外衣，还可以同时作为防潮衣膜和美学外衣。
防潮衣膜和美学外衣可以由同一个水溶性包衣膜提供，也可以由不同的水溶性包衣膜提供。防潮衣膜和美学外衣分别提供，其中的一些实施例中，美学外衣位于防潮衣膜的外侧。
在本申请中，防潮衣膜为可选结构，可有可无。当设置防潮衣膜时，其可以与带释药孔的控释衣层层叠设置，并位于控释衣层远离含药层的一侧表面上。
在本申请中，美学外衣为可选结构，可有可无。当设置美学外衣时，其可以与带释药孔的控释衣层层叠设置，并位于控释衣层远离含药层的一侧表面上。
在一些实施方式中，水溶性包衣膜的增重为片芯和带释药孔的控释衣层的重量之和的8％～20％，还可以选自如下任一种百分数或任两种百分数构成的区间：8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％等，还可以选自10％～20％、10％～18％等。在本申请中，水溶性包衣膜可改善制剂外观，以增加患者服药的顺应性，同时可提供颜色标识。水溶性包衣膜的组分可以选自着色剂、增塑剂、遮光剂、抗黏剂、溶剂等中的一种或者多种。
在一些实施例中，防潮衣膜可以包括本领域的技术人员所熟知的欧巴代、色缤兰以及其他可以形成防潮衣的包衣粉。
在本申请一些实施方式中，控释衣层和水溶性包衣膜依次层叠设置，可参阅图2。在一些实施例中，水溶性包衣膜的增重为片芯和带释药孔的控释衣层的重量之和的5～20％。
释放性质
在一些实施方式中，将渗透泵控释制剂在37℃、100rpm条件下控制释放，渗透泵控释制剂中的药物活性成分的释放行为满足如下的一个或多个释放性质：
于4小时时点的释放度大于4％；
于12小时时点的释放度大于40％；和
于24小时时点的释放度大于90％；
可选地，释放介质可以为900mL的1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液、900mL的不含胰酶的人工肠液、500mL的0.1mol/L盐酸溶液、900mL的0.1mol/L盐酸溶液或500mL的0.2％(w/v)氯化钠的0.1mol/L盐酸溶液。该渗透泵控释制剂可以包含前述任意合适的药物活性成分，包括但不限于硝苯地平、格列吡嗪、盐酸奥昔布宁、甲磺酸多沙唑嗪和帕利哌酮中的任一种或任意多种的组合。此时，可避免普通口服制剂血药浓度波动较大现象，减少服药次数，提高药物的安全性、有效性和顺应性。这里的“盐酸溶液”指以水为溶液的包含盐酸的溶液，可选由盐酸和水组成的盐酸水溶液。
进一步地，在一些实施方式中，渗透泵控释制剂中的药物活性成分的释放行为满足如下的一个或多个释放性质：
于4小时时点的释放度为4％～40％；
于12小时时点的释放度为40％～85％；和
于24小时时点的释放度大于90％。
在另一些实施方式中，渗透泵控释制剂中的药物活性成分的释放行为满足如下的一个或多个释放性质：
于4小时时点的释放度为4％～30％；
于12小时时点的释放度为40％～85％；和
于24小时时点的释放度大于90％。
在另一些实施方式中，渗透泵控释制剂中的药物活性成分的释放行为满足如下的一个或多个释放性质：
于4小时时点的释放度为4％～20％；
于12小时时点的释放度为40％～80％；和
于24小时时点的释放度大于90％。
在一些实施方式中，1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液介质采用如下方式配制：按7.15％磷酸氢二钠-2.1％枸橼酸(77.3∶22.7的体积比v/v)配制，pH＝6.8，将此缓冲液按10倍体积比稀释后使用(可以用水稀释)。
本申请提供的渗透泵控释制剂能够在一定时间范围内以恒定的释药速率释放药物。
在一些实施方式中，以药物活性成分为硝苯地平为例，渗透泵控释制剂在900mL的1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液介质中，37℃，桨法，100rpm下，于4小时、12小时、24小时时点的释放度，分别可达4％～20％、40％～80％、>90％，可避免普通口服制剂血药浓度波动较大现象，减少服药次数，提高药物的安全性、有效性和顺应性。可参考图3。
在一些实施方式中，以药物活性成分为格列吡嗪为例，渗透泵控释制剂在900mL的不含胰酶的人工肠液中，37℃，桨法，50rpm下，于4小时、12小时、24小时时点的释放度，分别可达4％～40％、40％～85％、>90％，可避免普通口服制剂血药浓度波动较大现象，减少服药次数，提高药物的安全性、有效性和顺应性。可参考图6。
在一些实施方式中，以药物活性成分为盐酸奥昔布宁为例，渗透泵控释制剂在500mL的0.1mol/L盐酸溶液中，37℃，桨法，50rpm下，于4小时、12小时、24小时时点的释放度，分别可达4％～20％、40％～80％、>90％，可避免普通口服制剂血药浓度波动较大现象，减少服药次数，提高药物的安全性、有效性和顺应性。可参考图7。
在一些实施方式中，以药物活性成分为甲磺酸多沙唑嗪为例，渗透泵控释制剂在900mL的0.1mol/L盐酸溶液中，37℃，桨法，75rpm下，于4小时、12小时、24小时时点的释放度，分别可达4％～30％、40％～85％、>90％，可避免普通口服制剂血药浓度波动较大现象，减少服药次数，提高药物的安全性、有效性和顺应性。可参考图8。
在一些实施方式中，以药物活性成分为帕利哌酮为例，渗透泵控释制剂在500mL的0.2％(w/v)氯化钠的0.1mol/L盐酸溶液中，37℃，桨法，50rpm下，于4小时、12小时、24小时时点的释放度，分别可达4％～30％、40％～85％、>90％，可避免普通口服制剂血药浓度波动较大现象，减少服药次数，提高药物的安全性、有效性和顺应性。可参考图9。
在本申请的第二方面，提供一种渗透泵控释组合物，其由本申请的第一方面的渗透泵控释制剂的各组分组成，可用于制备本申请的第一方面的渗透泵控释制剂。
在本申请的第三方面，提供一种渗透泵控释制剂的制备方法，可用于制备本申请的第一方面渗透泵控释制剂，该制备方法依次包括如下步骤：
S100：根据含药层的各组分制备含药层颗粒，根据助推层的各组分制备助推层颗粒；
S200：将含药层颗粒以及助推层颗粒在模具中压制成片芯；
S300：在片芯外表面包被控释衣层，然后在控释衣层上打孔，形成带释药孔的控释衣层；
S400：可选地，包被水溶性包衣膜。
步骤S100包括子步骤S110和S120。S110，根据含药层的各组分制备含药层颗粒；S120，根据助推层的各组分制备助推层颗粒。两个子步骤S110和S120之间并无顺序限制。
在一些实施方式中，提供一种渗透泵控释制剂的制备方法，依次包括如下步骤：①制备含药层颗粒，并制备助推层颗粒；②将含药层颗粒与助推层颗压制成双层片芯；③在片芯外表面包控释衣层；④在控释衣层上打孔，形成连接含药层和外部的释药孔；⑤可选地，在带释药孔的控释衣层外包水溶性包衣膜(如防潮衣膜)。
在一些实施方式中，提供一种渗透泵控释制剂的制备方法，按照制备工序的先后，包含如下制备步骤：(1)含药组合物颗粒制备；(2)助推层颗粒制备；(3)双层片芯的压制；(4)控释衣包衣；(5)包衣片打孔；(6)水溶性包衣膜的包被(如有)。
在一些实施方式中，提供一种渗透泵控释制剂的制备方法，包含如下制备步骤：
(1)含药层颗粒的制备
避光操作。将处方量的过60目筛的药物与含药层辅料混合均匀，加入流化床中，喷入80％乙醇-水溶液制粒，至适宜粒度时停止制粒，干燥，过20目筛整粒，加入硬脂酸镁，混匀，备用。
(2)助推层颗粒的制备
将处方量过60目筛的助推层辅料混合均匀后，加入流化床，喷入水溶液制粒，至适宜粒度时，停止制粒，进行干燥；过20目筛整粒，加入硬脂酸镁，混匀，备用。
(3)片芯的压制
避光操作。将上述制备完成的含药层、助推层颗粒加入双层压片机的料斗中，采用双层压片机压制成硬度适宜的双层片芯；测定双层片芯的硬度、含量和含量均匀度。
(4)控释衣包衣
按照实施例处方组成，配制控释半透膜包衣液；将上述检验合格的双层片芯用控释半透膜包衣液进行包衣，包衣后的产品在50℃条件下，干燥12小时，除去多余的有机溶剂和水分。
(5)包衣片打孔
将上述检验合格的包衣片，采用激光打孔机或者机械的方式，在片剂的含药层表面打一个直径为0.6～1.0mm的释药孔。
(6)包被水溶性包衣膜，如防潮衣膜包衣(如有)
将包衣粉(如防潮衣包衣粉)分散于水中，使溶解，配成固含量为5-15％的衣包衣溶液。打孔片置高效包衣锅中，采用上述配制好的包衣液进行包衣，至预定包衣增重；60℃条件下，干燥2小时，除去多余的水分，即得渗透泵控释制剂。
在本申请的第四方面，提供助推层组合物，其由促渗透聚合物、水不溶性膨胀聚合物、渗透压促进剂和药用辅料F2组成；其中，
所述促渗透聚合物、所述水不溶性膨胀聚合物、所述渗透压促进剂和所述药用辅料F2的定义如本申请的第一方面中所定义。
在一些实施例中，促渗透聚合物为海藻酸盐和羟乙基纤维素的组合。海藻酸盐的定义如前所述。在一些实施例中，海藻酸盐为海藻酸钠。
本申请所提供的推层组合物，由特定的促渗透聚合物(可选为海藻酸盐和羟乙基纤维素的组合，其中的海藻酸盐如海藻酸钠)以及合适的水不溶性膨胀聚合物(包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的至少一种，进一步如包括羧甲基淀粉钠和低取代羟丙基纤维素中的至少一种，更进一步如羧甲基淀粉钠和/或低取代羟丙基纤维素，可以为羧甲基淀粉钠，也可以为低取代羟丙基纤维素，还可以为羧甲基淀粉钠和低取代羟丙基纤维素的组合)、渗透压促进剂和其他助推层辅料(药用辅料F2)组成，所形成的高强度高韧性的水凝胶，有助于改善助推层组合物的力学性能，推动含药层药物和辅料，以受控的释药速率，经控释衣层中的释药孔释放，而且可以保障含药层活性成分的匀速释放，提高药物的最终释放量(24小时时点释放度＞90％)，有助于药物实现完全释放。该助推层组合物可适用于多种活性成分，包括但不限于格列吡嗪、盐酸奥昔布宁、甲磺酸多沙唑嗪和帕利哌酮的制备和控释给药，可以在不同溶出介质中均实现活性成分的稳定控制释放，且释药完全。
与传统的渗透泵控释片相比，采用前述意外发现的推层组合物制备得到的渗透泵控释制剂还具有如下有益效果：辅料稳定性良好，不易在制备过程中聚集，产品中活性成分的释放更稳定，片间释放度差异小。
在本申请的第五方面，提供本申请的第一方面的渗透泵控释制剂作为口服控释制剂的应用。
在一些实施方式中，渗透泵控释制剂是口服控释片。进一步地，规格为200～1000mg/片。每片的重量还可以选自如下任一种或任两种构成的区间：200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg、950mg、1000mg等。
在本申请的第六方面，提供本申请的第一方面的渗透泵控释制剂，或者本申请的第二方面渗透泵控释组合物，或者本申请的第四方面的助推层组合物在制备预防和/或治疗心血管疾病的药物中的应用，可选地，药物活性成分为硝苯地平。
在本申请中，如无其他说明，“预防和/或治疗心血管疾病”指预防心血管疾病和治疗心血管疾病中至少一方面。
在一些实施例中，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛(劳累性心绞痛)中的至少一种。
在一些实施例中，所述心血管疾病为高血压或冠心病慢性稳定型心绞痛。
在本申请的第七方面，提供一种心血管疾病的预防方法，包括给予受试者预防有效量的本申请第一方面所述渗透泵控释制剂，或者给予受试者预防有效量的本申请第二方面所述渗透泵控释组合物。
可选地，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种。
在本申请的第八方面，提供一种心血管疾病的质量方法，包括给予受试者治疗有效量的本申请第一方面所述渗透泵控释制剂，或者给予受试者治疗有效量的本申请第二方面所述渗透泵控释组合物。
可选地，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种。
在本申请的第九方面，提供用于预防心血管疾病和治疗心血管疾病中至少一方面的渗透泵控释制剂，所述渗透泵控释制剂如本申请第一方面所定义。
在本申请的第十方面，提供用于预防心血管疾病和治疗心血管疾病中至少一方面的渗透泵控释组合物，所述渗透泵控释组合物如本申请第一方面所定义。
本申请的第七方面、第八方面、第九方面、第十方面中，心血管疾病的定义可以如本申请第第六方面所定义。
在本申请中，如无其他说明，疾病的“预防”是指防止疾病或病症的发生或发展。
在本申请中，如无其他说明，疾病的“治疗”是指减轻、延缓进展、衰减，或维持现有疾病或病症，治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。
在本申请中，“药物”包括在体内或体外提供生理作用和药理作用中至少一方面的任何药剂、化合物、组合物或混合物，且往往提供的是有益效果。“药物”在体内产生生理作用的范围和在体内产生药理作用的范围均没有特别限制，各自独立地可以为全身效果，也可以只在局部产生效果。
本申请中，“受试者”是动物，可以优选为哺乳动物，进一步可以优选地为人。受试者包括但不限于具有疾病、病症和相关症状中至少一项的患者或者这些患者的潜在人群。“这些患者的潜在人群”是下述一类人群：虽然不具有疾病、病症和相关症状，尚未确定为“患者”， 但具有发展为“患者”的风险或可能。
本申请中，如无其他说明，术语“哺乳动物”主要是指温血脊椎类哺乳动物，包括但不限于：如猫、狗(犬)、兔、熊、狐狸、狼、猴子、鹿、鼠(如大鼠、小鼠)、猪、牛、羊、马、人等，可以优选灵长类动物，进一步可以优选为人。
前述任一方面中的一些实施方式中，受试者为人或者犬。
本申请中，“患者”是指一种动物，可以优选为哺乳动物，如人，又如犬。
在本申请中，如无其他说明，“预防有效量”是指针对疾病、病症和相关症状中至少一项的发生或发展，将引起个体的生物学或医学响应的药物活性成分的量，例如为个体带来生理上和药理上至少一方面积极效果的药物活性成分的量。
在本申请中，如无其他说明，“治疗有效量”是指针对疾病、病症和相关症状中至少一项，将引起个体的生物学或医学响应的药物活性成分的量，例如为个体带来生理上和药理上至少一方面积极效果的药物活性成分的量，所述生理上和药理上至少一方面积极效果包括但不限于降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等。
本申请的第七方面、第八方面、第九方面、第十方面中的制剂或组合物的给予方式，各自独立地可以为口服，可以不限于此。
以下提供一些实施例。
下面将结合实施例对本申请的实施方案进行详细描述。以下实施例记载了本申请示例性处方组成、制备方法和质量标准结果。应理解，这些实施例仅用于说明本申请而不用于限制本申请的范围。下列实施例中未注明条件的实验方法，优先参考本申请中给出的指引，还可以按照本领域的实验手册或常规条件，还可以按照制造厂商所建议的条件，或者参考本领域已知的实验方法。
下述的实施例中，涉及原料组分的量度参数，如无特别说明，可能存在称量精度范围内的细微偏差。涉及温度和时间参数，允许仪器测试精度或操作精度导致的可接受的偏差。
以下各例中，
(1)原辅料：
硝苯地平，来自陕西西岳制药有限公司的微粉化产品；
聚维酮K90和共聚维酮VA64，来自BASF的药用级辅料；
微粉硅胶，来自赢创特种化学(上海)有限公司，药用级；
海藻酸钠和海藻酸钾，来自美国杜邦或青岛明月海藻集团有限公司，食品或药用级；
羟乙基纤维素，亚什兰(中国)投资有限公司，药用级；
羧甲基淀粉钠，来自安徽山河辅料有限公司，药用级；
低取羟丙基纤维素，选自日本信越化学工业株式会社，药用级；
醋酸纤维素，伊士曼公司，药用级；
羟丙甲纤维素，美国杜邦公司；
红氧化铁：上海一品颜料有限公司，药用级；
氯化钠：江苏省勤奋药业有限公司；
硬脂酸镁：曲阜市天利药用辅料有限公司，药用级。
(2)设备：
片剂硬度仪：天津市天大天发科技有限公司，YD-20KZ；
流化床：创志机电科技发展有限公司，FLZB-0.5；
压片机：山东新马制药装备有限公司，SMA S60；
高效包衣机：创志机电科技发展有限公司，CHC-38；
激光打孔机：南京瑞驰电子技术工程有限公司，RC-YW-30；
高效液相色谱仪：安捷伦科技(中国)有限公司，Agilent 1260。
(3)试剂：
十二烷基硫酸钠：国药集团化学试剂有限公司，分析纯；
氯化钠：国药集团化学试剂有限公司，分析纯；
盐酸：国药集团化学试剂有限公司，分析纯
磷酸氢二钠：国药集团化学试剂有限公司，分析纯
其他如枸橼酸、胰酶等皆购自国药集团化学试剂有限公司。
以下各例中，如无其他说明，所使用的1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液介质采用如下方法配制得到：按7.15％磷酸氢二钠-2.1％枸橼酸(77.3:22.7体积比v/v)配制，pH＝6.8，将此缓冲液用水按10倍体积比稀释后使用。
1.制备实施例
1.1.制剂配方
(1)处方1：
(2)处方2：
(3)处方3：

(4)处方4：
(5)处方5：
(6)处方6：

(7)处方7：
(8)处方8：
(9)处方9：

(10)处方10：
(11)处方11：
(12)处方12：
(13)处方13：
(14)处方14：
(15)对比处方1：
(16)对比处方2：
(17)对比处方3：
(18)对比处方4：
(19)对比处方5：
(20)对比处方6：
(21)对比处方7
(22)对比处方8
2.制备工艺
2.1.各处方例
为了制备各处方例中的双层渗透泵控释片，按照制备工序的先后，包含如下制备步骤：(1)含药组合物颗粒制备；(2)助推层颗粒制备；(3)片芯的压制；(4)控释衣包衣；(5)包衣片打孔；(6)水溶性防潮衣的包被(如有)。
(1)含药层颗粒的制备
避光操作。将处方量的过60目筛药物与含药层的辅料混合均匀，加入流化床中，喷入80％乙醇-水溶液制粒，至适宜粒度时停止制粒，干燥，过20目筛整粒，加入硬脂酸镁，混匀，备用。
(2)助推层颗粒的制备
将处方量过60目筛的助推层辅料混合均匀后，加入流化床，喷入水溶液制粒，至适宜粒度时，停止制粒，进行干燥；过20目筛整粒，加入硬脂酸镁，混匀，备用。
(3)片芯的压制
避光操作。将上述制备完成的含药层、助推层颗粒分别加入到双层压片机的料斗中，采用双层压片机压制成硬度适宜的双层片芯；测定双层片芯的硬度、含量和含量均匀度。
(4)包隔离衣(若涉及)
按照实施例处方组成，配制隔离衣水溶液；将上述检验合格的双层片芯用隔离衣包衣液进行 包衣，包衣后的产品在50℃条件下，干燥12小时，除去多余的水分。
(5)控释衣包衣
按照实施例处方组成，配制控释半透膜包衣液；将上述检验合格的双层片芯用控释半透膜包衣液进行包衣，包衣后的产品在50℃条件下，干燥12小时，除去多余的有机溶剂和水分。
(6)包衣片打孔
将上述检验合格的包衣片采用激光打孔机或者机械的方式，在片剂的含药层表面打一个直径为0.6～1.0mm的释药孔。
(7)水溶性包衣膜包衣(如涉及)
将包衣粉分散于水中，使溶解，配成固含量为5-15％的衣包衣溶液。将上述打孔片置高效包衣锅中，采用上述配制好的包衣液进行包衣，至预定包衣增重；60℃条件下，干燥2小时，除去多余的水分，即得渗透泵控释片。
2.2.各对比处方例
根据前述的对比处方例的配方，采用与制备处方例渗透泵控释片相同的方法制备。
3.实验例
(1)实验实施例1：制备实施例处方1～10和对比处方1～8于900mL介质中释放度的测定
避光操作。取本品，照中国药典2020版四部附录0931溶出度与释放度测定第二法装置，将片子放入小金属网篮内，以1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液〔按7.15％磷酸氢二钠-2.1％枸橼酸(77.3:22.7体积比v/v)配制，pH＝6.8，将此缓冲液用水按10倍(体积比)用水稀释后使用〕900mL为释放介质，转速为每分钟100转，依法操作，分别于2小时、4小时、8小时、12小时、16小时、20小时、24小时各取溶液8mL，用0.45μm的微孔滤膜滤过，作为供试品溶液；同时补充相同温度、相同体积的释放介质。另取硝苯地平对照品约18mg，精密称定，置50mL棕色量瓶中，加甲醇30mL溶解，加水稀释至刻度，摇匀；精密量取5mL，置50mL棕色量瓶中，用1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液稀释至刻度，摇匀，作为对照品溶液。精密量取对照品溶液和供试品溶液各25μL，注入高效液相色谱，按外标法以峰面积计算出每片在不同时间的释放量。
HPLC检测色谱条件如下：色谱柱采用十八烷基键合硅胶柱，流动相为甲醇：水(50:50)，流速为1.0mL/min,检测波长为235nm。
表1.制备实施例处方1～10于900mL介质中的释放情况(n＝6)
表2.制备实施例比对处方1～8控释片在900mL介质中释放情况(n＝3)
表3.制备实施例处方1控释片在900mL介质中释放的片间差异(n＝6)
表4.制备实施例对比处方2控释片在900mL介质中释放的片间差异(n＝6)
由表1和表2结果可见，根据本申请的处方组成制备而成的控释片，24h释放度均＞90％。而以羟丙甲纤维素和/或共聚维酮为促渗透聚合物的对比处方1和比对处方3，以及以海藻酸钠和卡波姆为促渗透聚合物的对比处方2，24小时释放量均＜90％。但对比对方2片芯处方外包一层隔离衣后，再包被控释衣膜所制备的对比处方4控释片，释放度有显著改善，24h释放度达94.1％。
另外，与处方8相比(24h释放94.7％)，对比处方5-对比处方8控释片的24h释放低于90％，可见，在特定的处方组成下，单独使用羟乙基纤维素或海藻酸钠，或以常规的聚合物替代羟乙基纤维素或海藻酸钠中的一种，皆可能导致最终释放度的降低。羟乙基纤维素与海藻酸钠的助推层组合，在无隔离衣的结构下，有助于含药层药物的控制释放，可显著改善片剂的最终释放度。以上各处方片剂的释放度曲线，见图3和图4。
表3和表4的结果显示，与采用羟乙基纤维素与海藻酸钠组合的处方1相比，以卡波姆等为促渗透聚合物的对比处方2的片间释放差异明显增加，这可能是由于对比处方2助推层中的卡波姆在混粉或制粒过程中聚集不能均匀分散，导致助推层均一性不佳(图5)，部分区域助推层中胶凝强度不足导致片剂释放不均衡，片间差异大。可见，羟乙基纤维素与海藻酸钠的组合，形成的高强度高韧性水凝胶，有助于改善助推层组合物的力学性能，保障含药层活性成分的匀速释放，提高药物的最终释放量。
(2)实验实施例2：制备实施例处方11～处方14释放度测定
①制备实施例处方11释放度研究：取待测控释片，按照中国药典2020版四部附录0931溶出度与释放度测定第二法装置，将片子放入小金属网篮内，以不含胰酶的人工肠液900mL为溶剂，转速为每分钟50转，依法操作，在4小时、8小时、12小时、16小时和24小时时分别取溶液8mL，用0.45μm微孔滤膜滤过，取续滤液作为释放度供试品溶液，并即时在操作容器中补充上述溶剂8mL。
另取格列吡嗪对照品约50mg，精密称定，置100mL量瓶中，加甲醇20mL，超声使溶解，用甲醇稀释至刻度，摇匀，作为贮备液；取1mL储备液，置100mL量瓶中，以不含胰酶的人工肠液为溶剂，稀释至刻度，制备格列吡嗪对照品溶液。
分别取对照溶液和供试品溶液，照分光光度法，在276nm的波长处分别测定吸收度，以外标法计算出每片在不同时间的释放量。
释放度结果：制备实施例处方11格列吡嗪控释片的释放曲线图见图6。
②制备实施例处方12释放度研究：取待测控释片，照中国药典2020版四部附录0931溶出度与释放度测定第二法装置，将片子放入小金属网篮内，以0.1M的盐酸溶液500mL为释放介质，转速为每分钟50转，依法操作，经4小时、8小时、12小时、16小时与24小时时，各取溶液8mL，离心(8000rpm，15min)，取上清液作为供试品溶液，并及时补充相同体积的释放介质。另精密称取盐酸奥昔布宁对照品约12.5mg，置50mL量瓶中，加乙腈溶解并稀释至刻度，摇匀。精密量取该溶液1mL，置25mL量瓶中，加0.1M的盐酸溶液稀释至刻度，摇匀，作为对照品溶液；精密量取上述对照品和供试品溶液各50μL，注入液相色谱仪，进行测定，按外标法以峰面积计算出每片在不同时间的释放量。
HPLC检测色谱条件如下：色谱柱采用十八烷基硅烷键合硅胶柱；以乙腈-0.035M的磷酸盐缓冲液(取磷酸二氢钠4.83g，三乙胺5mL，加水至1000mL，用磷酸调节pH值至2.2±0.05)(35：65体积比)为流动相；检测波长为220nm；流速为1.5mL/min；进样量10μL。
释放度结果：制备实施例处方12盐酸奥昔布宁控释片的释放曲线图见图7。
③制备实施例处方13释放度研究：取待测控释片，照中国药典2020版四部附录0931溶出度与释放度测定第二法装置，将片子放入小金属网篮内，以0.1mol/L的盐酸溶液900mL为释放介质，转速为每分钟75转，依法操作，经4小时、8小时、12小时、16小时、24小时时，各取溶液10mL，离心(8000rpm，15min)，取上清液作为释放度供试品溶液，并同时补充相同体积的释放介质。
另取甲磺酸多沙唑嗪对照品约10mg，精密称定，置50mL量瓶中，加甲醇20mL，超声处理，使溶解，用甲醇稀释至刻度，摇匀；精密量取上述溶液10mL，置100mL量瓶中，以0.1mol/L的盐酸溶液稀释至刻度，摇匀，作为贮备液；取贮备液5mL，置25mL量瓶中，以0.1mol/L的盐酸溶液为溶剂，稀释成甲磺酸多沙唑嗪对照品溶液。
取供试品溶液和对照品溶液，照紫外-可见分光光度法(中国药典2005年版二部附录ⅣA)，在245nm的波长处分别测定吸光度，计算出每片在不同时间的释放量。
释放度结果：制备实施例处方13甲磺酸多沙唑嗪控释片的释放曲线图见图8。
④制备实施例处方14释放度研究：取待测控释片，照中国药典2020版四部附录0931溶出度与释放度测定第二法装置，将片子放入小金属网篮内，以0.2％(w/v)氯化钠的盐酸溶液(盐酸浓度约为0.1mol/L)500mL为释放介质，转速为每分钟50转，依法操作，经2小时、4小时、8小时、12小时、14小时与24小时，各取溶液8mL，离心(8000rpm，15min)，取上清液作为供试品溶液；同时补充相同体积的释放介质。另取帕利哌酮对照品适量，精密称定，加甲醇溶解并稀释制成每1mL中含帕利哌酮60μg的溶液，作为对照品储备液；精密量取对照品储备溶液适量，加0.2％氯化钠(w/v，％)的盐酸溶液制成每1mL中含帕利哌酮12μg的溶液，作为对照品溶液。
精密量取对照品溶液和供试品溶液各20μL，注入液相色谱仪，记录色谱图，按外标法以峰面积计算每片在不同时间的释放量。
HPLC检测色谱条件如下：色谱柱以十八烷基硅烷键合硅胶为填充剂；以甲醇-甲酸铵缓冲液(pH3.3±0.1)(取甲酸铵4.2g，加水适量使溶解，加甲酸5mL，加水稀释至4000mL)＝35：65为流动相；检测波长为275nm；流速为每分钟1.0mL，进样量20μL。
释放度结果：制备实施例处方14帕利哌酮控释片的释放曲线图见图9。
可见，采用本申请所述的助推层组合物，有助于改善助推层组合物的力学性能，在水性介质中，可形成高强度高韧性的水凝胶；本申请提供的助推层组合物可适用于多种活性成分(包括格列吡嗪、盐酸奥昔布宁，甲磺酸多沙唑嗪，帕利哌酮等)的控释给药，可在不同的溶出介质中均可实现活性成分的完全释药。
(3)实验实施例3：制备实施例处方1和对比处方2于100mL介质中的释放度测定
避光操作。取控释片，将片子放入小金属网篮内，以1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液〔按7.15％磷酸氢二钠-2.1％枸橼酸(77.3∶22.7的体积比v/v)配制，pH＝6.8，将此缓冲液按10倍体积比用水稀释后使用〕100mL为释放介质，转速为每分钟50转，依法操作，分别于4小时、8小时、12小时、16小时、24小时各取溶液8mL，用0.45μm的微孔滤膜滤过，同时补充相同温度、相同体积的释放介质，取上述续滤液，按体积比稀释10倍，作为供试品溶液。
另取硝苯地平对照品约18mg，精密称定，置50mL棕色量瓶中，加甲醇30mL溶解，加水稀释至刻度，摇匀；精密量取5mL，置50mL棕色量瓶中，用1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液稀释至刻度，摇匀，作为对照品溶液。
精密量取对照品溶液和供试品溶液各25μL，注入高效液相色谱仪，采用十八烷基键合硅胶柱，流动相为甲醇：水＝50:50，流速为1.0mL/min，检测波长为235nm，按外标法以峰面积计算出每片在不同时间的累积释放量。
表5.制备实施例处方1硝苯地平控释片在100mL介质中的释放情况(n＝6)
表6.制备实施例对比处方2硝苯地平控释片在100mL介质中的释放情况(n＝6)
由表5、表6和图10结果可见，在较低介质体积下(100mL)进行释放度测定，对比处方2的硝苯地平控释片的片间释放差异与处方1相比更大，对比处方2采用海藻酸钠、卡波姆和共聚维酮VA64的常规组合，在未包隔离衣情况下，存在释放不完全的现象(＜90％)，推测其在肠段下端(水分含量相对低的肠段)，吸收相对更差。
(4)实验实施例4：制备实施例处方2和对比处方2于不同浓度乙醇溶液中的释放度考察
避光操作。取待测控释片，将片子放入小金属网篮内，将配制好的含有1％十二烷基硫酸钠的缓冲液分别加入5％、10％、20％、40％(v/v)的无水乙醇，混合均匀后，以900mL分别作为5％、10％、20％、40％乙醇剂量倾泻考察释放介质，转速为每分钟100转，依法操作，于2小时、4小时、8小时和12小时，各取溶液8mL，用0.45μm的微孔滤膜滤过，作为供试品溶液；同时补充相同温度、相同体积的释放介质。另取硝苯地平对照品约18mg，精密称定，置50mL棕色量瓶中，加甲醇30mL溶解，加水稀释至刻度，摇匀；精密量取5mL，置50mL棕色量瓶中，用释放介质稀释至刻度，摇匀，作为对照品溶液。精密量取对照品溶液和供试品溶液各25μL，注入高效液相色谱，采用十八烷基键合硅胶柱，流动相为甲醇：水＝50:50，流速为1.0mL/min,检测波长为235nm。
结果见图11和图12，不同浓度的乙醇对本申请控释片释放速率有影响，在前2小时的释放有加快趋势。处方2和对比处方2在不同浓度乙醇的释放介质中的释放趋势基本一致，与pH6.8中释放情况相仿，对比处方2在不同浓度乙醇中的片间释放差异更大。
(5)实验实施例5：制备实施例处方2和对比处方3在pH6.8人工肠液中的释放度考察
参考中国药典2020版四部附录0921，配制pH6.8的模拟人工肠液，配制方法如下：取磷酸二氢钾6.8g，加水500mL使溶解，用0.1mol/L氢氧化钠溶液调节pH值至6.8，加入10g吐温80，使分散溶解；另取胰酶10g，加水适量使溶解，将两种溶液混合，加水稀释至1000mL，即得。
避光操作。取待测控释片，采用上述模拟肠液900mL为释放介质，转速为每分钟100转，依法操作，于4小时、8小时、12小时、16小时、24小时，各取溶液8mL，用0.45μm的微孔滤膜滤过，同时补充相同温度、相同体积的释放介质；8000rpm离心10min，去上清液作为供试品溶液。另取硝苯地平对照品约30mg，精密称定，置100mL棕色量瓶中，加甲醇50mL溶解，加水稀释至刻度，摇匀；精密量取5mL，置50mL棕色量瓶中，用释放介质稀释至刻度，摇匀，作为对照品溶液。精密量取对照品溶液和供试品溶液各25μL，注入高效液相色谱，采用十八烷基键合硅胶柱，流动相为甲醇：水(50:50)，流速1.0mL/min,检测波长为235nm，按外标法以峰面积计算出每片在不同时间点的累积释放量。
结果显示(图13)，与制备实施例的处方2相比，对比处方3的24小时释放度偏低，不能完全释放。本申请的控释片(处方2)在模拟肠液中的药物释放更稳定。
(6)实验实施例6：制备实施例处方6和对比处方3的犬药代动力学研究
由北京玛斯生物技术有限公司提供的健康Beagle犬12只，体质量10.3～12.5kg，实验动物饲养采用明暗各12小时的照明控制，温度22±1℃，湿度60±5％。空腹12小时(期间自由饮水)，分别给予处方6和对比处方3的硝苯地平控释片1片，于0.5小时、1小时、2小时、4小时、6 小时、8小时、10小时、12小时、16小时、24小时、48小时的时间点分别取血，血样于4000rpm下离心，血浆置于-80℃冰箱保存，以LC-MS(液相色谱/质谱)进行血药浓度分析，绘制药动曲线，统计药动参数。实验过程中，收集Beagle犬排出体外的控释片壳，测定片芯中残留药物的含量。
取上述排出体外的包衣片，用刀片切开成4瓣，充分暴露片芯内容物，置100mL棕色量瓶，加甲醇-水(50:50体积比)使充分溶解，定容，摇匀，采用0.45μm微孔滤膜滤过，作为供试品溶液。另取硝苯地平对照品18mg，精密称定，置100mL棕色量瓶中，加甲醇50mL溶解，加水稀释至刻度，摇匀，作为对照品溶液。精密量取对照品溶液和供试品溶液各25μL，注入高效液相色谱，采用十八烷基键合硅胶柱，流动相为甲醇：水＝(50:50体积比)，流速为1.0mL/min,检测波长为235nm。
表7.制备实施例处方6的硝苯地平控释片犬口服给药后血药浓度测定结果
表8.制备实施例对比处方3的硝苯地平控释片犬口服给药后血药浓度测定结果
表9.Beagle犬体内药动测定结果
制备实施例处方6和对比处方3的犬药动研究结果见表7、表8、表9和图14，处方6的硝苯地平控释片，相对于对比处方3片剂，在犬的体内吸收个体差异更小。采用本申请的助推层组合物，有助于改善助推层组合物的力学性能，在水性介质中，助推层聚合物可形成高强度高韧性的水凝胶，有利于实现片间更稳定的释放，片芯残留药物更少，释药更完全，具有更好的体内释放均一性。
处方6相对于对比处方3的硝苯地平控释片，在体内吸收后的Cmax更高，AUC更高，这可能是由于本申请的助推层组合物可实现更加均一和完全的释放，有利于药物在体内完全吸收。
(7)实验实施例7：制备实施例处方4、处方5、处方8、对比处方2、对比处方5的片芯质量考察
助推层促渗剂、水不溶性聚合物和渗透压促进剂，如海藻酸钠、羧甲基纤维素钠、氯化钠等的辅料的粘合力低，压制的片芯脆碎度较差，在后续的包衣工序中，助推层容易在滚动包衣过程中，因片间的碰撞而破碎损失，导致包衣失败，或片间释放差异。
本研究将上述不同实施例的含药层和助推层颗粒所压制的双层片芯，置于包衣锅内(创志CHC-38)，调整包衣参数(主机转速20rpm、入风温度30℃、喷雾压力0.05MPa)，分别于滚动5分钟、10分钟、30分钟取样，称重，并计算脆碎度(计算公式：损失重量/原重量×100％)。
结果可参阅表10和图15所示，滚动30min后的片剂外观可参阅图15。不含羟乙基纤维素的处方(比对处方5)，在包衣锅内滚动后的脆碎度明显最大，滚动30min后脆碎度达近4.3％；以共聚维酮VA64作为粘合剂的比对处方2，在包衣锅内滚动后脆碎度情况，相对有改善，但滚动30min后的脆碎度仍近1.2％。
使用羟乙基纤维素的处方4、处方5和处方8片芯，随着羟乙基纤维素用量的加大，在包衣锅内滚动后的脆碎度良好，滚动30min后的脆碎度分别为0.4％、0.2％和0.1％。
可见，在制备工艺方面，羟乙基纤维素的加入还有助于改善含药层和助推层所压制片芯的脆碎度，能够增加双层片芯的质量稳定性，减小包衣工序过程中助推层因片间脆碎度差异导致的片芯质量差异，改善产品批内释放差异大的缺陷。
表10.不同处方在包衣锅内包衣脆碎度
以上各实施方式和实施例的各技术特征可以进行任意合适方式的组合，为使描述简洁，未对上述实施方式和实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为在本说明书记载的范围中。
以上各实施例仅表达了本申请的几种实施方式，便于详细地理解本申请的技术方案，但并不能因此而理解为对本申请保护范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。此外应理解，在阅读了本申请的上述讲授内容之后，本领域技术人员可以对本申请作各种改动或修改，得到的等价形式同样落于本申请的保护范围。还应当理解，本领域技术人员在本申请提供的技术方案的基础上，通过合乎逻辑的分析、推理或者有限的试验得到的技术方案，均在本申请所附权利要求的保护范围内。因此，本申请专利的保护范围应以所附权利要求的内容为准，说明书及附图可以用于解释权利要求的内容。

Claims (30)

  1. 一种渗透泵控释制剂，其包括由内至外依次排列的如下结构：
    包括含药层和助推层构成的片芯；
    带释药孔的控释衣层；和
    可选的水溶性包衣膜；
    其中，所述释药孔连通所述含药层和所述渗透泵控释制剂的外部；所述助推层位于所述含药层远离所述释药孔的一侧；
    其中，所述含药层由药物活性成分、亲水性聚合物载体和药用辅料F1组成；其中，所述药用辅料F1为不同于所述亲水性聚合物载体的药用辅料；
    所述助推层由促渗透聚合物、水不溶性膨胀聚合物、渗透压促进剂和药用辅料F2组成；其中，所述促渗透聚合物包含羟乙基纤维素和海藻酸盐；所述水不溶性膨胀聚合物包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的一种或多种；其中，所述药用辅料F2为不同于所述促渗透聚合物、所述水不溶性膨胀聚合物及所述渗透压促进剂的药用辅料。
  2. 如权利要求1所述渗透泵控释制剂，其中，所述促渗透聚合物包含羟乙基纤维素和海藻酸盐，所述水不溶性膨胀聚合物为羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的任一种或者其组合；或者，
    所述促渗透聚合物为羟乙基纤维素和海藻酸盐，所述水不溶性膨胀聚合物包括羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的至少一种；或者，
    所述促渗透聚合物为羟乙基纤维素和海藻酸盐，所述水不溶性膨胀聚合物为羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的任一种或者其组合。
  3. 如权利要求1或2所述渗透泵控释制剂，其满足如下特征中的一项或多项：
    基于所述含药层的总重量，药物活性成分占所述含药层重量的4％～33％，所述亲水性聚合物载体占所述含药层重量的40％～96％(可选为40％～95％，另可选为40％～94％，另可选为65％～96％，另可选为65％～94％，另可选为65％～85％)，所述药用辅料F1占所述含药层重量的0～2％；
    基于所述助推层的总重量，所述促渗透聚合物占所述助推层重量的11％～66％(可选为12％～65％，另可选为20％～65％、另可选为11％～50％，另可选为20％～50％，另可选为20％～40％)，所述水不溶性膨胀聚合物占所述助推层重量的12％～71％(可选为13％～70％，进一步可选为15％～60％，更进一步可选为20％～50％，更进一步可选为20％～40％)，所述渗透压促进剂占所述助推层重量的10％～45％(可选为14％～42％，进一步可选为15％～40％)，所述药用辅料F2占所述助推层重量的0.5％～2.5％；
    所述含药层和所述助推层的重量比值为0.5～2，可选为0.8～1.6，另可选为0.8～1.5，另可选为0.9～1.5；
    所述带释药孔的控释衣层，增重为所述片芯重量的6％～25％，可选为6％～21％，另可选为8～25％，另可选为8％～15％，另可选为10％～20％。
  4. 如权利要求1～3中任一项所述渗透泵控释制剂，其中，基于所述含药层的总重量，药物活性成分占所述含药层重量的4％～33％，所述亲水性聚合物载体占所述含药层重量的40％～96％(可选为40％～95％，另可选为40％～94％，另可选为65％～96％，另可选为65％～94％，另可选为65％～85％)，所述药用辅料F1占所述含药层重量的0～2％；
    基于所述助推层的总重量，所述促渗透聚合物占所述助推层重量的11％～66％(可选为12％～65％，另可选为20％～65％、另可选为11％～50％，另可选为20％～50％，另可选为20％～40％)，所述水不溶性膨胀聚合物占所述助推层重量的12％～71％(可选为13％～70％，进一步可选为15％～60％，更进一步可选为20％～50％，更进一步可选为20％～40％)，所述渗透压促进剂占所述助推层重量的10％～45％(可选为14％～42％，进一步可选为15％～40％)，所述药用辅料F2占所述助推层重量的0.5％～2.5％；
    所述含药层和所述助推层的重量比值为0.5～2，可选为0.8～1.6，另可选为0.8～1.5，另可选为0.9～1.5；
    所述带释药孔的控释衣层的增重为所述片芯重量的6％～25％，可选为6％～21％，另可选为8～25％，另可选为8％～15％，另可选为10％～20％。
  5. 如权利要求1～4中任一项所述渗透泵控释制剂，其中，在所述片芯与所述的控释衣层之间不包括隔离衣膜。
  6. 如权利要求1～5中任一项所述渗透泵控释制剂，其满足如下特征中的一项或多项：
    所述助推层中不包含聚氧化乙烯；
    所述助推层中不包含卡波姆；
    所述促渗透聚合物中的海藻酸盐选自海藻酸钠、海藻酸钾和海藻酸铵中的一种或多种。
  7. 如权利要求1～6中任一项所述渗透泵控释制剂，其满足如下特征中的一项或多项：
    所述释药孔的数量为一个或多个，任一个所述释药孔连通所述含药层和所述渗透泵控释制剂的外部；
    所述释药孔的直径为0.6～1.0mm。
  8. 如权利要求1～7中任一项所述渗透泵控释制剂，其中，所述含药层满足如下特征中的一项或多项：
    所述亲水性聚合物载体为聚维酮、共聚维酮或者其组合；
    所述药用辅料F1选自助渗剂、抗静电剂和润滑剂中的一种或多种。
  9. 如权利要求8所述渗透泵控释制剂，其中，所述含药层满足如下特征中的一项或多项：
    所述助渗剂选自氯化钠、氯化钾、山梨醇、木糖醇、葡萄糖和蔗糖中的一种或多种，可选为氯化钠；
    所述抗静电剂包括微粉硅胶、硬脂酸和聚乙二醇中的一种或者多种，可选为微粉硅胶；所述润滑剂选自硬脂酸镁、聚乙二醇、硬脂富马酸钠和滑石粉中的一种或多种。
  10. 如权利要求1～9中任一项所述渗透泵控释制剂，其中，在所述助推层中，所述促渗透聚合物主要包含羟乙基纤维素和海藻酸盐；
    可选地，所述羟乙基纤维素和所述海藻酸盐的重量之和在所述促渗透聚合物中的重量占比大于80％。
  11. 如权利要求10所述渗透泵控释制剂，其中，所述助推层满足如下特征中的一项或多项：
    所述助推层中，所述羟乙基纤维素和所述海藻酸盐的重量比为1:(1～60)，可选为1:(1.5～40)，进一步可选为1:(1.5～25)，更进一步可选为1:(1.5～20)，更进一步可选为1:(1.5～16)；
    所述羟乙基纤维素在所述助推层中的重量占比为0.4％～22％(可选为0.5～20％)。
  12. 如权利要求1～11中任一项所述渗透泵控释制剂，其中，在所述助推层中，所述药用辅料F2选自润滑剂、着色剂和助流剂中的一种或多种。
  13. 如权利要求1～12中任一项所述渗透泵控释制剂，其中，在所述助推层中，所述水不溶性膨胀性聚合物包括羧甲基淀粉钠和低取代羟丙基纤维素中的至少一种，还可选地包含交联羧甲基纤维素钠和交联聚维酮中的一种或多种。
  14. 如权利要求1～13中任一项所述渗透泵控释制剂，其中，在所述助推层中，所述渗透压促进剂选自氯化钠、氯化钾、氯化镁、山梨醇、木糖醇、葡萄糖和蔗糖中的一种或多种，可选为氯化钠。
  15. 如权利要求1～14中任一项所述渗透泵控释制剂，其中，所述带释药孔的控释衣层由半透性控释衣膜材料和可选的药用辅料F3组成；其中，所述药用辅料F3为增塑剂和致孔剂中的一种或多种。
  16. 如权利要求15所述渗透泵控释制剂，其满足如下特征中的一项或多项：
    所述半透性控释衣膜材料为醋酸纤维素或含有醋酸纤维素的预混包衣粉；
    所述药用辅料F3选自聚乙二醇、邻苯二甲酸二乙酯、柠檬酸三乙酯、三醋酸甘油酯和癸二酸二丁酯中的一种或多种；
    所述药用辅料F3相对于所述半透性控释衣膜材料和所述药用辅料F3的重量之和的重量比为0～20％，可选为1％～10％，另可选为1％～7.4％。
  17. 如权利要求1～16中任一项所述渗透泵控释制剂，其中，所述水溶性包衣膜的增重为所述片芯和所述带释药孔的控释衣层的重量之和的5％～20％。
  18. 如权利要求1～17中任一项所述渗透泵控释制剂，其中，所述药物活性成分选自硝苯地平、格列吡嗪、盐酸奥昔布宁、甲磺酸多沙唑嗪和帕利哌酮中的任一种。
  19. 如权利要求18所述渗透泵控释制剂，其中，所述药物活性成分为硝苯地平。
  20. 如权利要求1～19中任一项所述渗透泵控释制剂，其中，所述含药层和所述助推层构成双层片芯。
  21. 如权利要求1～20中任一项所述渗透泵控释制剂，其中，将所述渗透泵控释制剂在37℃、100rpm条件下控制释放，所述渗透泵控释制剂中的药物活性成分的释放行为满足如下的一个或多个释放性质：
    于4h时点的释放度大于4％；
    于12h时点的释放度大于40％；和
    于24h时点的释放度大于90％；
    可选地，释放介质为900mL的1％十二烷基硫酸钠的磷酸盐-枸橼酸缓冲液、900mL的不含 胰酶的人工肠液、500mL的0.1mol/L盐酸溶液、900mL的0.1mol/L盐酸溶液或500mL的0.2％(w/v)氯化钠的0.1mol/L盐酸溶液。
  22. 一种渗透泵控释组合物，其由权利要求1～21中任一项所述渗透泵控释制剂的各组分组成，用于制备所述渗透泵控释制剂。
  23. 权利要求1～21中任一项所述渗透泵控释制剂的制备方法，其依次包括如下步骤：
    根据所述含药层的各组分制备含药层颗粒，根据所述助推层的各组分制备助推层颗粒；
    将所述含药层颗粒以及所述助推层颗粒在模具中压制成所述片芯；
    在所述片芯的外表面包被控释衣层，然后在所述的控释衣层上打孔，形成所述带释药孔的控释衣层；
    可选地，包被所述水溶性包衣膜。
  24. 一种助推层组合物，其由促渗透聚合物、水不溶性膨胀聚合物、渗透压促进剂和药用辅料F2组成；其中，
    所述促渗透聚合物、所述水不溶性膨胀聚合物、所述渗透压促进剂和所述药用辅料F2的定义如权利要求1～21中任一项所定义；
    可选地，所述促渗透聚合物为羟乙基纤维素和海藻酸盐的组合。
  25. 权利要求1～21中任一项所述渗透泵控释制剂作为口服控释制剂的应用。
  26. 权利要求1～21中任一项所述渗透泵控释制剂，或者权利要求22所述渗透泵控释组合物，或者权利要求24所述助推层组合物在制备预防心血管疾病和治疗心血管疾病中至少一方面的药物中的应用，其中，所述药物活性成分为硝苯地平，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种。
  27. 一种心血管疾病的预防方法，包括给予受试者预防有效量的权利要求1～21中任一项所述渗透泵控释制剂，或者给予受试者预防有效量的权利要求22所述渗透泵控释组合物；
    可选地，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种。
  28. 一种心血管疾病的治疗方法，包括给予受试者治疗有效量的权利要求1～21中任一项所述渗透泵控释制剂，或者给予受试者治疗有效量的权利要求22所述渗透泵控释组合物；
    可选地，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种。
  29. 用于预防心血管疾病和治疗心血管疾病中至少一方面的渗透泵控释制剂，所述渗透泵控释制剂如权利要求1～21中任一项所定义；
    可选地，所述心血管疾病包括高血压和冠心病慢性稳定型心绞痛中的至少一种。
  30. 用于预防心血管疾病和治疗心血管疾病中至少一方面的渗透泵控释组合物，所述渗透泵控释组合物如权利要求22所定义。
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CN113730370A (zh) * 2021-10-22 2021-12-03 河南省人民医院 一种琥珀酸舒马普坦缓释片及其制备方法
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CN101167700A (zh) * 2006-10-24 2008-04-30 北京红林制药有限公司 硝苯地平控释片及其制备方法
CN101496792A (zh) * 2008-01-30 2009-08-05 中国科学院上海药物研究所 普萘洛尔或其盐的迟释制剂及其制备方法
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