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WO2024160220A1 - 一种布立西坦双释三层片及其制备方法 - Google Patents

一种布立西坦双释三层片及其制备方法 Download PDF

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WO2024160220A1
WO2024160220A1 PCT/CN2024/074852 CN2024074852W WO2024160220A1 WO 2024160220 A1 WO2024160220 A1 WO 2024160220A1 CN 2024074852 W CN2024074852 W CN 2024074852W WO 2024160220 A1 WO2024160220 A1 WO 2024160220A1
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release
layer
sustained
brivaracetam
release layer
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PCT/CN2024/074852
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English (en)
French (fr)
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叶小妹
盘永健
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泰州越洋医药开发有限公司
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Publication of WO2024160220A1 publication Critical patent/WO2024160220A1/zh

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    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention relates to pharmaceutical technology, in particular to a brivaracetam dual-release three-layer tablet and a preparation method thereof.
  • Brivaracetam chemical name (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide, molecular formula C 11 H 20 N 2 O 2 .
  • Brivaracetam is an effective drug for the treatment of epilepsy. It is clinically used as a monotherapy for partial-onset epilepsy patients aged 4 years and above. Brivaracetam is easily soluble in water and weakly acidic liquids. Its effective blood concentration in the body is maintained for a short time. The currently available brivaracetam tablets and oral solutions need to be administered twice a day.
  • brivaracetam In the existing reports on the release behavior of brivaracetam, such as CN106692095A, CN201510202995, and CN114028343A, rapid-release preparations of brivaracetam are disclosed. Such preparations have the same shortcomings as the marketed preparations, namely, the drug release rate is too fast, the blood drug concentration fluctuates greatly and is difficult to control, the adverse reactions are obvious, the toxic and side effects are large, the number of dosing times is large, and the compliance is poor; while CN113908153A and CN102046153B disclose sustained-release preparations of brivaracetam. Although such preparations last longer, they take effect slowly and have limited therapeutic effects.
  • the present invention provides a brivaracetam tablet and a preparation process thereof.
  • a brivaracetam dual-release three-layer tablet characterized in that it is made of three layers stacked together, namely, a quick-release layer, a retardation layer and a sustained-release layer; wherein the retardation layer does not contain a drug and is located in the middle; at least 60% of the area of each side of the quick-release layer and the sustained-release layer that is in contact with the retardation layer is covered by the retardation layer;
  • the sustained-release material in the blocking layer contains a waxy sustained-release material;
  • the API is selected from one, two or more of brivaracetam, a pharmaceutically acceptable complex of brivaracetam, a pharmaceutically acceptable salt of brivaracetam, a pharmaceutically acceptable solvate of brivaracetam, a pharmaceutically acceptable hydrate of brivaracetam, and other related structural derivatives of levetiracetam;
  • the tablets have the following characteristics: in the paddle method, 50 rpm, and pH 1.2, pH 4.5, pH 6.8 or aqueous medium, the dissolution of the raw material drug is not less than 25% after half an hour of tableting, 30-65% after 2 hours, not less than 65% after 6 hours, not less than 80% after 14 hours, and less than 100%; and zero-order release is shown after half an hour of tableting.
  • the brivaracetam dual-release three-layer tablet is characterized in that the content of the raw material drug in the immediate-release layer accounts for 20-35% of the total amount of the raw material drug, preferably 25-30%; the content of the raw material drug in the sustained-release layer accounts for 65-80% of the total amount of the raw material drug, preferably 70-75%.
  • the weight proportion of the disintegrant in the quick-release layer is 2% to 7.5%, preferably 5%; the disintegrant is one or more of cross-linked carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose. This selection ensures that the quick-release part is quickly released and effective in the gastrointestinal environment.
  • the weight ratio of the filler in the immediate release layer is 40-85%, and one or more of lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and corn starch are used; preferably, the filler is a combination of anhydrous calcium hydrogen phosphate and corn starch, or a combination of microcrystalline cellulose and lactose; preferably, the weight ratio of the combination of microcrystalline cellulose and lactose is 1:1-1:3, and the optimal ratio is 1:1. This selection ensures that the particles of the immediate release layer have good compressibility and fluidity, and obtains tablets with good consistency.
  • the weight proportion of the adhesive in the quick-release layer is 3-8%, and the adhesive is selected from hydroxypropyl cellulose or povidone K30 aqueous solution.
  • the waxy sustained-release material is selected from one or more of glyceryl behenate, carnauba wax and cetyl alcohol;
  • the sustained-release material in the blocking layer is composed of a waxy sustained-release material and a swelling-type sustained-release material, wherein the weight ratio of the waxy sustained-release material to the swelling-type sustained-release material is 0.4-0.8, preferably 0.5-0.7; and the sum of the weights of the two accounts for greater than or equal to 60% of the blocking layer prescription;
  • the swelling sustained-release material is selected from one or more of guar gum, vegetable gum, alginate, hydroxypropyl methylcellulose, hydroxymethyl cellulose or hydroxyethyl cellulose.
  • the thickness of the blocking layer is greater than or equal to 1 mm; preferably, the thickness is 1 to 3 mm;
  • the filler accounts for 15-30% of the barrier layer, preferably 20-27%; lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate or mannitol are selected; microcrystalline cellulose and lactose are preferred; the binder is hydroxypropyl cellulose or povidone K30 aqueous solution, and the binder accounts for 6% to 15% of the prescription amount of the barrier layer to ensure proper fluidity during the preparation process.
  • the formulation of the sustained-release layer comprises active ingredients, sustained-release materials, fillers, glidants, and lubricants;
  • the sustained-release material accounts for 20% to 60% of the prescription amount, preferably 25% to 40%; the sustained-release material is HPMC K15M, HPMC K4M, HPMC K750, HPMC K100M, HPMC K100LV, Eudragit Any one or two of behenic acid glyceryl, xanthan gum; HPMC K100M and Eudragit A combination of HPMC K4M and Eudragit or HPMC K100M.
  • the filler accounts for 35-65% of the sustained-release layer weight, and is one or more of microcrystalline cellulose, lactose, anhydrous calcium hydrogen phosphate, corn starch, etc.
  • the present invention has found through research that the parameter selection ensures the compressibility and fluidity of the prescription and sufficient porosity after tableting.
  • any of the above-mentioned brivaracetam dual-release three-layer tablets is also provided with a film coating, wherein the coating material is a gastric soluble coating powder, and the coating weight gain is 2%-5%, preferably 3%.
  • the content of the raw material is not higher than 20%.
  • the present invention has found that the use of this parameter can ensure that the raw material is fully dispersed by the excipients, and can effectively avoid the API from being dissolved under pressure and sticking during the tableting process due to its low melting point.
  • Another aspect of the present invention provides a preparation process for any of the above-mentioned brivaracetam dual-release three-layer tablets, characterized in that the steps of a, weighing the raw materials brivaracetam, disintegrant, and filler required for the prescription amount of the immediate-release layer, and mixing them; adding a binder, wet granulating, drying after wet granulation, the moisture content of which is less than 4.0%, dry granulating, and mixing to obtain the immediate-release layer mixed granules;
  • Step b weighing the sustained-release material and filler required for the sustained-release layer prescription amount, and mixing them; adding an appropriate amount of purified water by atomization and liquid addition to wet granulate, drying after wet granulation, and performing dry granulation until the moisture content is less than 4.0%, and performing total mixing to obtain the sustained-release layer total mixed granules;
  • Step c weighing the sustained-release material and filler required for the prescription amount of the barrier layer, mixing them; adding a binder, wet granulating, drying after wet granulation, and drying the granules until the moisture content is less than 4.0%, and performing dry granulation, and performing total mixing to obtain the barrier layer total mixed granules;
  • the total mixing in step a is to take part of the immediate-release layer dry granules and mix them with the prescribed amount of glidant, sieve them, and then premix them with the remaining immediate-release layer dry granules; take part of the premix and mix it with the prescribed amount of lubricant, sieve it, and then mix it with the remaining premix to obtain the immediate-release layer total mixed granules;
  • the total mixing in step b is to take part of the sustained-release layer dry granules and mix them with the prescribed amount of glidant, sieve them, and then premix them with the remaining sustained-release layer dry granules; take part of the premix and mix it with the prescribed amount of lubricant, sieve it, and then mix it with the remaining premix to obtain the sustained-release layer total mixed granules;
  • the total mixing in step c is to take part of the blocking layer dry particles and mix them with the prescribed amount of glidant, sieve them, and then premix them with the remaining blocking layer dry particles; take part of the premixed mixture and mix it with the prescribed amount of lubricant, sieve them, and then mix them with the remaining premixed mixture to obtain the blocking layer total mixed particles;
  • the tableting order is sustained-release layer, barrier layer, and quick-release layer.
  • the present invention Compared with the existing brivaracetam sustained-release preparation technology, the present invention has developed a special barrier layer formulation, which is configured between the immediate-release layer and the sustained-release layer, so that the sustained-release layer in the present invention has one less release surface compared with ordinary sustained-release preparations.
  • the barrier layer can ensure that the release of the sustained-release layer is smoother and achieves the effect of zero-order release.
  • the API content of both the immediate-release layer and the sustained-release layer is not higher than 20%, ensuring that the API is fully dispersed by the excipients. This can effectively avoid the reduction of tablet weight consistency or dissolution consistency due to the low melting point of the API and its dissolution under pressure during the tableting process.
  • the test results show that the tablets provided by the present invention can dissolve not less than 25% of the raw material drug in half an hour, 30-60% of the raw material drug in 2 hours, not less than 60% in 6 hours, and not less than 80% in 14 hours, which is less than 100%; half an hour after tableting, it shows zero-order release, has good dissolution consistency, tablet weight consistency, takes into account both rapid onset and long-term slow release onset, and once-a-day administration can achieve drug treatment effectiveness.
  • Fig. 2 is the dissolution diagram of brivaracetam in Example 1 and Comparative Example 1;
  • Fig. 3 is the dissolution diagram of brivaracetam in Example 2 and Comparative Example 2;
  • FIG4 is a diagram showing the dissolution deviation of brivaracetam in Example 3 and Comparative Example 3;
  • Fig. 5 is the dissolution diagram of brivaracetam in Example 4 and Comparative Example 5;
  • Fig. 6 is the dissolution diagram of brivaracetam in Example 4 and Comparative Example 6;
  • FIG. 7 shows the dissolution diagram of brivaracetam in Example 5 and Comparative Example 7.
  • a. Weigh the raw materials brivaracetam, disintegrant and filler required for the prescription amount of the immediate-release layer, mix them; add a binder, perform wet granulation, dry the wet granules after drying, and make the moisture content less than 4.0% by dry granulation, and perform total mixing to obtain the immediate-release layer total mixed granules.
  • the total mixing is to take part of the immediate-release layer dry granules and mix them with the prescribed amount of glidant, sieve them, and then premix them with the rest of the immediate-release layer dry granules; take part of the premix and mix it with the prescribed amount of lubricant, sieve them, and then mix them with the rest of the premix to obtain the immediate-release layer total mixed granules.
  • sustained-release materials and fillers required for the sustained-release layer prescription amount and mix them add an appropriate amount of purified water by atomization and liquid addition for wet granulation, dry the wet granules after wet granulation, and make the moisture content less than 4.0% for dry granulation, and perform total mixing to obtain the sustained-release layer total mixed granules.
  • the total mixing is to take part of the sustained-release layer dry granules and mix them with the prescribed amount of glidant, sieve them, and then premix them with the rest of the sustained-release layer dry granules; take part of the premix and mix it with the prescribed amount of lubricant, sieve them, and then mix them with the rest of the premix to obtain the sustained-release layer total mixed granules.
  • the sustained-release materials and fillers required for the prescription amount of the barrier layer and mix them add the binder, perform wet granulation, dry the wet granules after drying, and make the moisture content less than 4.0% by dry granulation, and perform total mixing to obtain the barrier layer total mixed granules.
  • the total mixing is to take part of the barrier layer dry granules and mix them with the prescribed amount of glidant, sieve them, and then premix them with the rest of the barrier layer dry granules; take part of the premix and mix it with the prescribed amount of lubricant, sieve them, and then mix them with the rest of the premix to obtain the barrier layer total mixed granules.
  • the compression order of three-layer tablets can be: sustained-release layer>barrier layer>immediate-release layer, immediate-release layer>barrier layer>sustained-release layer, barrier layer>sustained-release layer>immediate-release layer;
  • Tables 8 to 11 list the comparative formulas that verify these influencing factors.
  • the sustained-release material used in the sustained-release layer of Comparative Example 1 is sodium carboxymethyl cellulose.
  • the ratio of the raw material of the immediate-release layer to the total amount of the raw material in the tablet is 12%, and the ratio of the raw material of the sustained-release layer to the total amount of the raw material in the tablet is 88%;
  • the proportion of the raw materials in the sustained-release layer in the tablets of Comparative Example 3 is greater than 20% of the total amount of the sustained-release layer prescription; compared with the tablets of Example 3, the proportion of the raw materials in the immediate-release layer in the tablets of Comparative Example 4 is greater than 20% of the total amount of the immediate-release layer prescription;
  • the ratio of the blocking layer wax (carnauba wax) to HPMC is 0.18 by weight; compared with the tablets of Example 4, in Comparative Example 6, the total amount of the blocking layer wax (carnauba wax) + HPMC in the blocking layer accounts for 47.06%.
  • Comparative Example 7 uses the total particles of the barrier layer prepared in Example 5 to press a barrier layer with a thickness of 0.8 mm, and the prescription is consistent with that of Example 5.
  • Comparative Example 8 The difference between Comparative Example 8 and Examples 5, 6 and 7 is that the ratio of microcrystalline cellulose to lactose in the immediate-release layer of Comparative Example 8 is 1:4, and the rest is consistent with Examples 5, 6 and 7.
  • Comparative Example 1 The difference between Comparative Example 1 and Example 1 is only that the sustained-release material is different.
  • Dissolution characteristics As shown in Figure 2, after switching to sodium carboxymethyl cellulose, the dissolution rate at each stage decreased, especially at the 6th hour. Afterwards, the comparative example 1 was significantly lower than the example 1, which would result in a low blood drug concentration in the sustained-release phase, making it difficult to achieve drug efficacy.
  • Example 1 the dissolution rate of the raw material drug is not less than 25% in half an hour, 30-65% in 2 hours, not less than 65% in 6 hours, not less than 80% in 14 hours, and less than 100%; and zero-order release is shown half an hour after tableting.
  • Comparative Example 2 The difference between Comparative Example 2 and Example 2 is that the API ratio in the immediate-release layer and the sustained-release layer is different, and the other excipients are completely the same.
  • the ratio of the API in the immediate-release layer to the total amount of the API in the tablet is 12% (less than 20%), and the ratio of the API in the sustained-release layer to the total amount of the API in the tablet is 88% (greater than 80%);
  • Dissolution characteristics As shown in Figure 3, after the API in the immediate release layer is reduced, it takes more than 25% 2 hours after tablet administration, which cannot achieve the effect of rapid onset of action.
  • Comparative Example 3 The only difference between Comparative Example 3 and Example 3 is the ratio of API to excipients in the sustained-release layer.
  • the filler content is reduced so that the API content ratio is increased from 19.7% to 21.31%, which is slightly higher than 20%.
  • Example 3 Six tablets of Example 3 and Comparative Example 3 were randomly selected and subjected to dissolution experiments.
  • the dissolution data of Example 3 are shown in Table 12, and the dissolution data of Comparative Example 3 are shown in Table 13.
  • the tablets in Comparative Example 3 do not meet the requirements of the present invention: the dissolution of the raw material drug is not less than 25% in half an hour, 30-65% in 2 hours, not less than 65% in 6 hours, and not less than 80% in 14 hours, which is less than 100%; and zero-order release is shown after half an hour of tableting.
  • Comparative Example 4 The only difference between Comparative Example 4 and Example 3 is that the API in the quick-release layer formulation in Comparative Example 4 is higher than 20%.
  • the present invention found that, as shown in the formulations of Comparative Example 4 and Example 3 and Table 14, when the API content in the immediate-release layer is higher, the layer weight is smaller, and the consistency of the tablet weight is worse.
  • Comparative Example 5 The only difference between Comparative Example 5 and Example 4 is that the ratio of the waxy sustained-release material to the swelling sustained-release material in the barrier layer is lower than 0.5.
  • the dissolution data are shown in Figure 5.
  • Comparative Example 6 i.e., Tablet 4
  • the ratio of the sustained-release material in the barrier layer is lower than 60% (the ratio in Example 4 is 64.12%), that is, the ratio of the filler and other auxiliary materials is increased.
  • Comparative Example 7 The difference between Comparative Example 7 and Example 5 is that the thickness of the retardation layer in Comparative Example 7 is 0.08 mm, while the thickness of the retardation layer in Example 5 is 2 mm;
  • the effect of the reduced mass specific gravity of the barrier layer on the dissolution characteristics of the tablet is mainly that it causes the dissolution to be too fast, which will lead to excessively high blood drug concentrations in the early stage and shorten the effective time.
  • Comparative Example 8 The difference between Comparative Example 8 and Examples 5, 6 and 7 is that the ratio of microcrystalline cellulose to lactose in the immediate-release layer is different, but the total amount of microcrystalline cellulose to lactose in the immediate-release layer remains unchanged.
  • the ratio of microcrystalline cellulose to lactose in Comparative Example 8 is 1:4, the ratio of microcrystalline cellulose to lactose in Example 5 is 1:2, the ratio of microcrystalline cellulose to lactose in Example 6 is 1:1, and the ratio of microcrystalline cellulose to lactose in Example 7 is 1:3.
  • the acute angle between the inclined surface of powder accumulation and the bottom horizontal plane is called the angle of repose.

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Abstract

一种布立西坦双释三层片剂及其制备方法，属于制药技术，其特征在于，由速释层、阻滞层和缓释层三层叠加制成；其中阻滞层不含药，且位于中间；速释层及缓释层各自与阻滞层接触的一面的至少75％的区域被所述阻滞层覆盖，且所述阻滞层中的缓释材料含有蜡质类缓释材料；所述片剂能显著改善布立西坦药物的释放特性、提高用药顺应性和安全性、优化该药物的治疗效果。

Description

一种布立西坦双释三层片及其制备方法 技术领域
本发明涉及制药技术，特别是一种布立西坦双释三层片及其制备方法
背景技术
布立西坦(brivaracetam),化学名称为(2S)‐2‐[(4R)‐2‐氧代‐4‐丙基四氢-1H-吡咯-1-基]丁酰胺((2S)-2-[(4R)‐2‐oxo‐4‐propyltetrahydro‐1H‐pyrrol‐1‐yl]butanamide)，分子式为C11H20N2O2。布立西坦是一种有效治疗癫痫症的药物，临床上作为4岁及以上部分发作型的癫痫患者的单药治疗。布立西坦属于易溶易水和弱酸性液体，其在体内有效血药浓度维持时间较短，现有上市布立西坦片剂和口服溶液，都需要一天两次给药。
对布立西坦的释放行为进行研究的现有报道中，如CN106692095A，CN201510202995，CN114028343A公开了布立西坦速释制剂，这类制剂与已上市制剂缺点一致，药物释放速率过快，血药浓度波动大不易控制，不良反应明显，毒副作用大，给药次数多，顺应性较差；而CN113908153A和CN102046153B公开了布立西坦缓释制剂，这类制剂虽持续时间较长，但起效较慢、治疗效果有限。
发明内容
为改善布立西坦药物的释放特性、提高用药顺应性和安全性、优化该药物的治疗效果，本发明提供了一种布立西坦片剂及其制备工艺。
本发明的第一方面，提供一种布立西坦双释三层片剂，其特征在于，由速释层、阻滞层和缓释层三层叠加制成；其中，阻滞层不含药，且位于中间；速释层及缓释层各自与阻滞层接触的一面的至少60％的区域被所述阻滞层覆盖；
且所述阻滞层中的缓释材料含有蜡质类缓释材料；所述原料药选自布立西坦、布立西坦的药学上可接受的配合物、布立西坦的药学上可接受的盐、布立西坦的药学上可接受的溶剂化物和布瓦西坦的药学上可接受的水合物、左乙拉西坦的其他相关结构衍生物中的一种、两种或更多种；
所述片剂具有以下特性：在桨法，50rpm，以及pH1.2、pH4.5、pH6.8或水介质中，投片半小时原料药溶出不低于25％、2小时原料药溶出30～65％、6小时溶出不低于65％、14小时溶出不低于80％，小于100％；且投片半小时之后呈零级释放。
所述的布立西坦双释三层片剂，其特征在于，所述速释层中原料药含量占原料药总量的20～35％，优选占25～30％；所述缓释层原料药含量占原料药总量的65～80％，优选占70～75％。
优选地，在所述速释层的处方中：
崩解剂在速释层中的重量比例的2％～7.5％，优选5％；；所述崩解剂采用交联羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮和低取代羟丙基纤维素中的一种或多种。该选择确保在肠胃环境下，速释部分迅速释放并起效。
填充剂在速释层中的重量比例为40～85％，采用乳糖、微晶纤维素、无水磷酸氢钙、玉米淀粉中的一种或多种；优选地，所述填充剂采用无水磷酸氢钙和玉米淀粉的组合，或者微晶纤维素和乳糖的组合；优选地，微晶纤维素和乳糖的组合中二者重量比例为1:1～1:3，最优为1:1。该选择保障速释层颗粒有较好的可压性流动性，获得一致性良好的片剂。
粘合剂在速释层中的重量比例3～8％，且粘合剂选用羟丙基纤维素或聚维酮K30水溶液。
优选地，所述蜡质类缓释材料选自山嵛酸甘油酯，巴西棕榈蜡和十六醇中的一种或多种；
优选地，所述阻滞层中的所述缓释材料由蜡质类缓释材料和溶胀型缓释材料组成，其中蜡质类缓释材料与溶胀型缓释材料的重量比例为0.4～0.8，优选重量比例为0.5～0.7；且二者质量之和在阻滞层处方中所占比例大于等于60％；
所述溶胀型缓释材料选自瓜尔胶、菜胶、海藻胶、羟丙甲纤维素、羟甲基纤维素或羟乙基纤维素中的一种或多种。
优选地，所述阻滞层厚度大于等于1mm；优选厚度为1～3mm；
优选地，填充剂在阻滞层中所占比例为15～30％，优选20～27％；选用乳糖、微晶纤维素、无水磷酸氢钙或甘露醇；优选微晶纤维素和乳糖；粘合剂选用羟丙基纤维素或聚维酮K30水溶液，粘合剂占阻滞层处方量的6％～15％，保障制备过程中恰好的流动性。
优选地，所述缓释层的处方中，包含活性成分、缓释材料、填充剂、助流剂、润滑剂；
其中缓释材料占处方量的20％～60％，优选最优25～40％；所述缓释材料采用HPMC K15M，HPMC K4M，HPMC K750，HPMC K100M、HPMC K100LV，尤特奇山嵛酸甘油酯，黄原胶中的任一种或两种；进一步优选HPMC K100M和尤特奇的组合，或HPMC K4M和尤特奇的组合，或HPMC K100M。
所述填充剂占缓释层层重35～65％，采用微晶纤维素、乳糖、无水磷酸氢钙、玉米淀粉等一种或多种。经研究本发明发现该参数选择确保处方的可压性和流动性以及压片后足够的孔隙率。
上述任一布立西坦双释三层片剂，还具有薄膜包衣，包衣材料选用胃溶型包衣粉，包衣增重为2％-5％，优选3％。
上述任一布立西坦双释三层片剂中，在所述速释层的处方或所述缓释层的处方中，原料药含量均不高于20％。经研究本发明发现采用该参数，能确保保障原料药被辅料充分分散，可有效避免压片过程中因API熔点低，受压溶解粘冲。
本发明的另一方面，提供上述任一布立西坦双释三层片剂的制备工艺，其特征在于，步骤a、称取速释层处方量所需的原料布立西坦、崩解剂、填充剂，进行混合；加入粘合剂，进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得速释层总混颗粒；
步骤b、称取缓释层处方量所需的缓释材料和填充剂，进行混合；以雾化加液方式加入适量纯化水进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得缓释层总混颗粒；
步骤c、称取阻滞层处方量所需的缓释材料和填充剂，进行混合；加入粘合剂，进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得阻滞层总混颗粒；
进一步地，步骤a中的总混为取部分速释层干颗粒与处方量的助流剂混合后，过筛，然后与其余速释层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得速释层总混颗粒；
进一步地，步骤b中的总混为取部分缓释层干颗粒与处方量的助流剂混合后，过筛，然后与其余缓释层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得缓释层总混颗粒；
进一步地，步骤c中的总混为取部分阻滞层干颗粒与处方量的助流剂混合后，过筛，然后与其余阻滞层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得阻滞层总混颗粒；
优选地，还包括压片步骤，压片顺序为缓释层、阻滞层、速释层。
与现有技术相比，本发明技术方案具有的优点。
1.结构上，既含速释部分，又含缓释部分，可达到现有布立西坦速释制剂迅速起效的效果，也可达到普通缓释制剂长时间平缓释放的效果，从而减少给药次数，提高患者顺应性，降低血药浓度波动过大引起的不良反应发生率。
与现有布立西坦缓释制剂技术相比，本发明研发了专用的阻滞层处方，配置速释层和缓释层之间，使得本发明中的缓释层相比于普通缓释制剂少一个释放面，该阻滞层能够确保缓释层的释放更平稳、达到零级释放的效果。
2.API分布方面，本发明速释API：缓释API＝20％～35％：65％～80％，可避免现有布立西坦速释制剂口服后血药峰浓度过高带来的副作用，也可避免现有布立西坦缓释片技术起效过慢的弊端。
3.速释层和缓释层API含量均不高于20％，确保原料药被辅料充分分散，可有效避免压片过程中因API熔点低，受压溶解粘冲，导致片重一致性或溶出一致性降低。
综上，测试结果显示，本发明提供的片剂都能够在半小时原料药溶出不低于25％、2小时原料药溶出30～60％、6小时溶出不低于60％、14小时溶出不低于80％，小于100％；投片半小时之后呈零级释放，具有良好的溶出一致性，片重一致性，兼顾快速起效和长时间平缓释放起效，一天一次给药即可实现药物治疗有效性。
附图说明
图1实施例1～7与对比例1～8的片剂结构；
图2实施例1与对比例1布立西坦溶出图；
图3实施例2与对比例2布立西坦溶出图；
图4实施例3与对比例3的布立西坦溶出偏差图；
图5实施例4与对比例5布立西坦溶出图；
图6实施例4与对比例6布立西坦溶出图；
图7实施例5与对比例7布立西坦溶出图。
具体实施方式
以下结合示例性实施方式对本发明的技术方案进行详细说明，但不应该理解为对本发明所请求的保护范围的限制。
实施例1～7.本发明示例性处方
对应实施例1～7的处方见表1～表7，制备方法步骤如下：
1.制备速释层总混颗粒、缓释层总混颗粒、阻滞层总混颗粒
a、称取速释层处方量所需的原料布立西坦、崩解剂、填充剂，进行混合；加入粘合剂，进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得速释层总混颗粒。
其中总混为取部分速释层干颗粒与处方量的助流剂混合后，过筛，然后与其余速释层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得速释层总混颗粒。
b、称取缓释层处方量所需的缓释材料和填充剂，进行混合；以雾化加液方式加入适量纯化水进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得缓释层总混颗粒。其中总混为取部分缓释层干颗粒与处方量的助流剂混合后，过筛，然后与其余缓释层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得缓释层总混颗粒。
c、称取阻滞层处方量所需的缓释材料和填充剂，进行混合；加入粘合剂，进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得阻滞层总混颗粒。其中，其中总混为取部分阻滞层干颗粒与处方量的助流剂混合后，过筛，然后与其余阻滞层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得阻滞层总混颗粒。
2.压片
三层片压片顺序可为：缓释层>阻滞层>速释层，速释层>阻滞层>缓释层，阻滞层>缓释层>速释层；
试验发现，以缓释层>阻滞层>速释层顺序压片所得三层片，一致硬度和体外溶出曲线溶出一致 性好。
表1.实施例1处方
表2.实施例2处方

表3.实施例3处方

表4.实施例4处方

表5.实施例5处方

表6.实施例6处方
表7.实施例7处方

二.测试
性能测试：
各阶段溶出度：投片后0.5h，2h，6h，14h，18h的体外溶出度
溶出一致性
片重一致性
体外溶出度，采用桨法，加沉降篮，50rpm,pH6.4磷酸缓冲液。
以下根据测试列出在研发中发现的对片剂的理化性质产生显著影响的因素及测试结果：其中表8～表11列出了验证这些影响因素的对比例处方。
对比例1
表8.对比例1处方
其中，对比例1与实施例1的片剂相比，缓释层中采用的缓释材料为羧甲基纤维素钠。
对比例2
表9.对比例2处方

对比例2与实施例2的片剂相比，速释层原料药与片剂中原料药总量比例为12％，缓释层原料药与片剂中原料药总量比例在88％；
对比例3～4
表10.对比例3～4处方

其中对比例3与实施例3的片剂相比，缓释层原料药占缓释层处方总量的比例大于20％；对比例4与实施例3的片剂相比，速释层原料药占速释层处方总量的比例大于20％；
对比例5～6
表11.对比例5～6处方

其中，对比例5与实施例4的片剂相比，按重量计，阻滞层蜡质(巴西棕榈蜡)与HPMC比值为0.18；对比例6与实施例4的片剂相比，阻滞层蜡质(巴西棕榈蜡)+HPMC的总量在阻滞层中比例为47.06％。
对比例7
对比例7与实施例5不同在于，对比例7取实施例5制得的阻滞层总颗粒压制厚度为0.8mm的阻滞层，处方与实施例5一致。
对比例8
对比例8和实施例5、实施例6、实施例7的不同在于，对比例8速释层的微晶纤维素和乳糖的比为1：4，其余与实施例5、实施例6、实施例7一致。
2.1缓释材料的影响
对比例1与实施例1中实施例1的区别仅在于缓释材料不同。
实施例1与对比例1的布立西坦溶出曲线如图2.
溶出特性：如图2所示，换成羧甲基纤维素钠后，各阶段溶出度都有所降低，尤其在第6小时 之后对比例1明显低于实施例1，这会导致缓释阶段血药浓度偏低，难以达到药效。
实施例1半小时原料药溶出不低于25％、2小时原料药溶出30～65％、6小时溶出不低于65％、14小时溶出不低于80％，且小于100％；且投片半小时之后呈零级释放。
2.2 API在缓释层和速释层中的分配比例的影响
对比例2与实施例2的区别仅仅在于速释层和缓释层中API比例不同，其它辅料完全一致。对比例2中：速释层原料药与片剂中原料药总量比例为12％(低于20％)，缓释层原料药与片剂中原料药总量比例为88％(高于80％)；
实施例2与对比例2的布立西坦溶出曲线如图3。
溶出特性：如图3所示，速释层中API降低后，投片2小时之后才达到25％以上，不能起到投药快速起效的作用。
而实施例2片剂2半小时原料药溶出度30％、2小时原料药溶出30～60％、6小时溶出不低于65％、14小时溶出不低于80％，小于100％；且投片半小时之后呈零级释放。
2.3缓释层中API含量的影响
对比例3与实施例3相比差别仅在于：缓释层中API与辅料的比例，对比例3中降低了填充剂含量使得API含量比例从19.7％提高到21.31％，稍微高于20％。
随机取实施例3和对比例3各6片片剂，分别进行溶出实验。实施例3的溶出数据如下表12,对比例3溶出数据见表13.
表12.实施例3，浆法50rpm，PH6.4，900ml,n＝6片，溶出度和溶出偏差
表13.对比例3，浆法50rpm，PH6.4，900ml,n＝6片，溶出度和溶出偏差

同时对比两类药片的溶出偏差曲线如图4。
如表13所示，对比例3中的药片均达不到本发明中的要求：半小时原料药溶出不低于25％、2小时原料药溶出30～65％、6小时溶出不低于65％、14小时溶出不低于80％，小于100％；且投片半小时之后呈零级释放
如图4所示，可以看出，对比例3的溶出偏差RSD较大。
可以确定缓释层中API的绝对含量不变，但是填充剂含量降低时，会显著影响药片溶出特性，相应影响血药浓度，即药物有效性、稳定性和安全性。
2.4速释层中API含量的影响
对比例4与实施例3相比差别仅在于，对比例4中速释层处方中API高于20％。
测试显示，片重一致性明显低于实施例3。
表14.
本发明发现，如对比例4与实施例3的配方及表14所示，当速释层中API含量越高，层重越小，片重一致性越差。
2.5阻滞层缓释材料构成比例的影响
对比例5与实施例4的区别仅在于阻滞层缓释材料中蜡质类与溶胀类缓释材料的比值低于0.5。
溶出度数据如图5所示。
如图5所示，当阻滞层缓释材料中蜡质类物质与溶胀类缓释材料的比值降低后，影响最明显的是各阶段溶出比例都显著高于实施例4的片剂，会导致前期血药浓度偏高同时药物作用时间缩短。
2.6阻滞层缓释材料含量的影响
对比例6与实施例4即片剂4的区别仅在于阻滞层缓释材料在阻滞层比值低于60％(实施例4中的比例为64.12％)，即提高了填充剂及其他辅料的比例。
溶出度数据如图6所示。
如图6所示，当阻滞层缓释材料总比例降低后，各阶段溶出比例都显著高于实施例4的片剂，溶出曲线在3小时后之后即趋于平坦，会导致释药前期血药浓度偏高，而后血药浓度又不能达到有效水平，不能真正兼顾到快速起效+长时间有效，实际上有效时间缩短。
2.7阻滞层厚度的影响
对比例7中与实施例5区别在于，对比例7阻滞层厚度为0.08mm，实施例5阻滞层厚度为2mm；
测试结果如图7所示：
如图7所示，阻滞层质量比重降低对片剂溶出特性的影响主要是导致溶出太快，会导致前期血药浓度过高，有效时间缩短。
2.8速释层微晶纤维素和乳糖的比值的影响
对比例8与实施例5、实施例6、实施例7区别在于速释层的微晶纤维素和乳糖的比值不同，但速释层微晶纤维素与乳糖的总量不变。对比例8微晶纤维素和乳糖的比值为1：4，实施例5微晶纤维素和乳糖的比值为1：2，实施例6微晶纤维素和乳糖的比值为1：1，实施例7微晶纤维素和乳糖的比值为1：3。
速释层颗粒的流动性如表15所示：
表15.
粉体堆积斜面与底部水平面所夹锐角叫做休止角。休止角越大，摩擦系数越大，粉体的流动性越差。一般认为休止角小于40°时粉体的流动性良好；豪斯纳比是指粉体的振实密度与松装密度之比。豪斯纳比越大，粉体的流动性越差。豪斯纳比大于1.35时，粉体的流动性差。如表15所示，对比例8的速释层颗粒经过粉体检测，休止角为44.7°，大于40°，豪斯纳比为1.41，大于1.35，粉体流动性差，而实施例5、实施例6、实施例7合格。

Claims (16)

  1. 一种布立西坦双释三层片剂，其特征在于，由速释层、阻滞层和缓释层三层叠加制成；其中
    阻滞层不含药，且位于中间；速释层及缓释层各自与阻滞层接触的一面的至少60％的区域被所述阻滞层覆盖；
    且所述阻滞层中的缓释材料含有蜡质类缓释材料；
    所述原料药选自布立西坦、布立西坦的药学上可接受的配合物、布立西坦的药学上可接受的盐、布立西坦的药学上可接受的溶剂化物和布立西坦的药学上可接受的水合物、左乙拉西坦的其他相关结构衍生物中的一种、两种或更多种；
    所述片剂具有以下特性：在桨法，50rpm，以及pH1.2、pH4.5、pH6.8或水介质中，投片半小时原料药溶出不低于25％、2小时原料药溶出30～65％、6小时溶出不低于65％、14小时溶出不低于80％但小于100％；且投片半小时之后体外呈零级释放。
  2. 根据权利要求1所述的布立西坦双释三层片剂，其特征在于，所述速释层中原料药含量占原料药总量的20～35％或25～30％；所述缓释层原料药含量占原料药总量的65～80％或70～75％。
  3. 根据权利要求1所述的布立西坦双释三层片剂，其特征在于，在所述速释层的处方中:
    崩解剂在速释层中的重量比例的2％～7.5％或5％，且崩解剂采用交联羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮和低取代羟丙基纤维素中的一种或多种；
    填充剂在速释层中的重量比例为40～85％，且填充剂采用乳糖、微晶纤维素、无水磷酸氢钙、玉米淀粉中的一种或多种；
    粘合剂在速释层中的重量比例3～8％，且粘合剂选用羟丙基纤维素或聚维酮K30水溶液。
  4. 根据权利要求3所述的布立西坦双释三层片剂，其特征在于，所述填充剂采用无水磷酸氢钙与玉米淀粉的组合，或者微晶纤维素与乳糖的组合。
  5. [根据细则26改正 16.04.2024]
    根据权利要求3所述的布立西坦双释三层片剂，其特征在于，所述微晶纤维素和乳糖的组合中二者重量比例为1:1～1:3。
  6. [根据细则26改正 16.04.2024]
    根据权利要求1所述的布立西坦双释三层片剂，其特征在于，所述蜡质类缓释材料选自山嵛酸甘油酯，巴西棕榈蜡和十六醇中的一种或多种。
  7. 根据权利要求1所述的布立西坦双释三层片剂，其特征在于，所述阻滞层中的所述缓释材料由蜡质类缓释材料和溶胀型缓释材料组成，其中蜡质类缓释材料与溶胀型缓释材料的重量比例为0.4～0.8或0.5～0.7；且二者质量之和在阻滞层处方中所占比例大于等于60％；
    其中所述溶胀型缓释材料选自瓜尔胶、菜胶、海藻胶、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素的一种或多种。
  8. 根据权利要求7所述的布立西坦双释三层片剂，其特征在于，所述阻滞层厚度大于1mm或等于1～3mm。
  9. 根据权利要求8所述的布立西坦双释三层片剂，其特征在于，填充剂在阻滞层中所占比例为15～30％或20～27％，所述填充剂选用乳糖、微晶纤维素、无水磷酸氢钙或甘露醇；
    粘合剂占阻滞层处方量的6～15％，选用羟丙基纤维素或聚维酮K30水溶液。
  10. 根据权利要求1所述的布立西坦双释三层片剂，其特征在于，所述缓释层的处方中，包含活性成分、缓释材料、填充剂、助流剂、润滑剂；
    其中所述缓释材料占处方量的20％～60％或25～40％；
    所述缓释材料采用HPMC K15M，HPMC K4M，HPMC K750，HPMC K100M、HPMC K100LV，山嵛酸甘油酯，黄原胶中的任一种或两种；
  11. 根据权利要求10所述的布立西坦双释三层片剂，其特征在于，所述缓释材料采用HPMC K100M和的组合，或HPMC K4M和的组合，或HPMC K100M；
    所述填充剂占缓释层层重的35～65％，所述填充剂采用微晶纤维素、乳糖、无水磷酸氢钙、玉米淀粉等一种或多种。
  12. 根据权利要求1～11任一所述的布立西坦双释三层片剂，其特征在于，在所述速释层的处方或所述缓释层的处方中，原料药含量均不高于20％。
  13. 根据权利要求1～11任一所述的布立西坦双释三层片剂，其特征在于，还具有薄膜包衣，包衣材料选用胃溶型包衣粉，包衣增重为2％～5％或3％。
  14. 权利要求1-13任一布立西坦双释三层片剂的制备工艺，其特征在于，采用以下步骤：
    步骤a、称取速释层处方量所需的原料布立西坦、崩解剂、填充剂，进行混合；加入粘合剂，进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得速释层总混颗粒；
    步骤b、称取缓释层处方量所需的缓释材料和填充剂，进行混合；以雾化加液方式加入适量纯化水进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得缓释层总混颗粒；
    步骤c、称取阻滞层处方量所需的缓释材料和填充剂，进行混合；加入粘合剂，进行湿法制粒，湿整粒后干燥，水分小于4.0％，进行干整粒，进行总混，得阻滞层总混颗粒。
  15. 根据权利要求14所述的制备工艺，其中
    步骤a中的总混为取部分速释层干颗粒与处方量的助流剂混合后，过筛，然后与其余速释层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得速释层总混颗粒；
    步骤b中的总混为取部分缓释层干颗粒与处方量的助流剂混合后，过筛，然后与其余缓释层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得缓释层总混颗粒；
    步骤c中的总混为取部分阻滞层干颗粒与处方量的助流剂混合后，过筛，然后与其余阻滞层干颗粒预混；取部分预混合物与处方量的润滑剂混合后，过筛，然后与其余预混合物进行总混，得阻滞层总混颗粒。
  16. 根据权利要求14所述的制备工艺，其中，还包括压片步骤，压片顺序为缓释层、阻滞层、速释层。
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CN102961354A (zh) * 2012-12-24 2013-03-13 中国药科大学 阿西美辛三层控释片及其制备方法
CN104188930A (zh) * 2014-08-25 2014-12-10 泰州越洋医药开发有限公司 一种阿西美辛三层控释片及其制备方法
CN115192572A (zh) * 2021-04-08 2022-10-18 成都同道慧宜生物医药科技有限公司 布立西坦药剂、其制备方法和应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102961354A (zh) * 2012-12-24 2013-03-13 中国药科大学 阿西美辛三层控释片及其制备方法
CN104188930A (zh) * 2014-08-25 2014-12-10 泰州越洋医药开发有限公司 一种阿西美辛三层控释片及其制备方法
CN115192572A (zh) * 2021-04-08 2022-10-18 成都同道慧宜生物医药科技有限公司 布立西坦药剂、其制备方法和应用

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