WO2015096668A1 - 一种双层片及其制备方法 - Google Patents

一种双层片及其制备方法 Download PDF

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WO2015096668A1
WO2015096668A1 PCT/CN2014/094367 CN2014094367W WO2015096668A1 WO 2015096668 A1 WO2015096668 A1 WO 2015096668A1 CN 2014094367 W CN2014094367 W CN 2014094367W WO 2015096668 A1 WO2015096668 A1 WO 2015096668A1
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Prior art keywords
layer
release
tablet
sustained
release layer
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PCT/CN2014/094367
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English (en)
French (fr)
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闻晓光
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Individual
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Priority claimed from CN201310716482.6A external-priority patent/CN103655505B/zh
Priority claimed from CN201310717968.1A external-priority patent/CN103690503B/zh
Priority claimed from CN201310718529.2A external-priority patent/CN103690505B/zh
Priority to EP14874251.3A priority Critical patent/EP3087980B1/en
Priority to JP2016543032A priority patent/JP6296371B2/ja
Priority to DK14874251.3T priority patent/DK3087980T3/en
Application filed by Individual filed Critical Individual
Priority to US15/107,892 priority patent/US10137092B2/en
Priority to ES14874251T priority patent/ES2712129T3/es
Publication of WO2015096668A1 publication Critical patent/WO2015096668A1/zh
Anticipated expiration legal-status Critical
Priority to US16/178,547 priority patent/US10925836B2/en
Priority to US16/178,543 priority patent/US10940114B2/en
Ceased legal-status Critical Current

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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
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/2095—Tabletting processes
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the application number is 201310717968.1 and the name is “ a method for preparing a two-layer sheet ”.
  • the application number is 201310718529.2 and the name is “ a sleeping double-layer controlled release tablet and a preparation method thereof ”
  • the bilayer tablet is a biphasic drug delivery system with a two-layer structure. It can not only combine the two drugs or the same drug in different release modes to achieve the desired pharmacokinetic behavior, but also improve the drug with compatible reaction.
  • the stability also gives the tablet a special function.
  • the present invention achieves the above object by designing a two-layer sheet of a new structure. Its technical solution is:
  • a two-layer tablet which is a two-layer release mode, is a combination of two layers of tablets, wherein one of the tablets has a hole. When the formulation is made, the pores have the composition of another layer of tablets.
  • Each of the above two layers comprises an active ingredient and an auxiliary material, wherein the active ingredient in each layer may be one or a combination of two or more active ingredients.
  • the active ingredients of the two layers in the double layer may be the same or different;
  • Each of the two layers of tablets may be an immediate release layer or a sustained release layer
  • the number of the pores is 1-3, preferably one.
  • the pores have a diameter of from 1 to 10 mm, preferably from 2 to 6 mm.
  • the two-layer sheet can also be subjected to coating treatment or the like according to a practical need in accordance with a conventional method in the art.
  • the preparation method of the above two-layer sheet is:
  • the component I and the component II are in the form of granules or powder;
  • the component I is formed into a sheet with a hole (hereinafter also referred to as a sheet I);
  • Second compression The component II and the above-mentioned sheet are pressed together to form a two-layer sheet composed of a layer of the component I and a layer of the component II, and the component II is filled into the pores of the sheet during the pressing.
  • the hole formed in the sheet I is formed by pressing with a model having a hole, or may be punched after tableting; in one example of the present invention, the component I is a sheet having a hole punched by an annular punch. .
  • An advantage of the present invention is that the component I layer of the two-layer sheet is perforated, and since the pores of the sheet I are filled with the component II, the thus obtained two-layer sheet is very strong and is not easily separated during storage and transportation. Its structure is shown in Figures 1-3.
  • the method for preparing a two-layer sheet of the present invention is suitable for the preparation of various types of two-layer sheets. Those skilled in the art can select various conventional pharmaceutical excipients according to actual needs.
  • the pharmaceutical excipient is preferably one or more of a sustained release material, a filler, a disintegrant, a lubricant, a binder, and a glidant.
  • the sustained-release material is preferably one or more of hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose; the filler is preferably one or more of lactose, pre-treated starch, and microcrystalline cellulose.
  • the disintegrating agent is preferably one or more selected from the group consisting of sodium carboxymethylcellulose, sodium carboxymethyl starch, and crospovidone; the lubricant is preferably one of stearic acid, magnesium stearate, and talc.
  • the binder is preferably one or more of povidone, hydroxypropylcellulose, hydroxypropylmethylcellulose; the glidant is preferably microsilica gel.
  • the weight percentage of each component in the component I in the present invention is preferably:
  • the weight percentage of each component in the II particles in the present invention is preferably:
  • the bilayer tablet of the present invention is also preferably coated, wherein the coating layer preferably contains the following components and percentages:
  • An analgesic double-layer controlled release tablet comprising an immediate release layer and a sustained release layer, wherein both the immediate release layer and the sustained release layer contain an analgesic active ingredient and a pharmaceutical auxiliary, wherein the sustained release layer has The pores are filled with particles of the immediate release layer drug, and the pores have a diameter of 2-6 mm.
  • the analgesic active ingredient is selected from the group consisting of aspirin, magnesium salicylate, sodium salicylate, magnesium choline salicylate, diflunisal, salsalate, ibuprofen, indomethacin, fluoride Biprofen, phenoxybuprofen, naproxen, nabumetone, piroxicam, phenylbutazone, diclofenac, fenprofen, ketoprofen, ketorolac, tetraclofenac, shu One or more of linoleic acid, tolmetine or anisodamine, or a derivative of the above compounds;
  • the active ingredient contained in the immediate release layer and the sustained release layer may be the same or different;
  • the medicinal adjuvant is selected from one or more of a filler, a disintegrant, a lubricant, a binder, and a glidant;
  • the filler is selected from one or more of lactose, lactose, pre-treated starch and microcrystalline cellulose;
  • the disintegrant is selected from one or more of sodium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, and crospovidone;
  • the lubricant is selected from one or more of stearic acid, magnesium stearate, and talc;
  • the binder is selected from one or more of povidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose;
  • the glidant is silica.
  • sustained-release layer in the analgesic double-layer sheet also contains a sustained-release material.
  • the sustained release material is selected from one or more of hydroxypropylmethylcellulose, ethylcellulose, hydroxypropylcellulose;
  • the double-layer controlled release tablet further comprises a coating layer, and the coating layer comprises the following components in percentage by weight:
  • sustained-release granules are pressed into a porous sustained-release layer, and the sustained-release layer is placed in a die of the tableting machine, and the immediate-release granules are filled for a second pressing to form an immediate release layer and a sustained-release layer.
  • the hypnotic agent is selected from the group consisting of zolpidem, zaleplon, zopiclone, triazolam, midazolam, flurazepam, diazepam, chlordiazepoxide, nitrazepam, estazolam , alprazolam or lorazepam, or one of the derivatives of the above compounds
  • the sustained release material is selected from one or more of hydroxypropylmethylcellulose, ethylcellulose or hydroxypropylcellulose;
  • the medicinal adjuvant is selected from the group consisting of a filler, a disintegrating agent, One or more of a lubricant, a binder, and a glidant.
  • the filler is selected from one or more of lactose, lactose, pre-treated starch and microcrystalline cellulose; the disintegrant is selected from the group consisting of sodium carboxymethyl cellulose and cross-linked carboxymethyl fiber.
  • the disintegrant is selected from the group consisting of sodium carboxymethyl cellulose and cross-linked carboxymethyl fiber.
  • One or more of sodium, sodium carboxymethyl starch and crospovidone; the lubricant is selected from one or more of stearic acid, magnesium stearate and talc;
  • the binder is selected from one or more of povidone, hydroxypropylcellulose, and hydroxypropylmethylcellulose; the glidant is silica.
  • the sustained release layer comprises the following components in percentage by weight:
  • the preparation method of the above-mentioned sleeping double-layer controlled release tablet comprises the following steps:
  • sustained-release granules are pressed into a porous sustained-release layer, and the sustained-release layer is placed in a die of the tableting machine, and the immediate-release granules are filled for a second pressing to form an immediate release layer and a sustained-release layer.
  • the coating and the coating layer are formulated and prepared in the same manner as the above-mentioned analgesic double-layer controlled release tablets.
  • one of the two-layer sheets has a hole
  • the hole is filled with the composition of the other layer during the tableting process, so that the two-layer sheet is tightly bonded and is not easily separated during storage and transportation.
  • the double-layer controlled release tablet is tested by a dissolution test to detect that the release time of the immediate release layer is 10 to 30 seconds, and the sustained release layer has a zero-order release mode, that is, The release of the drug is approximately constant, which helps to maintain a stable blood concentration in the body, which greatly improves the effectiveness and safety of the patient.
  • Figure 1 is a schematic view showing the structure of a two-layer sheet with a hole
  • Figure 2 is a schematic view showing the structure of a two-layer sheet with two holes
  • Figure 3 is a schematic structural view of a two-layer sheet with three holes
  • 1 is a sheet I
  • 2 is a sheet II
  • 3 is a hole
  • Figure 4 is a two-layer dissolution profile of the sleeping tablet of Example 1 (where the four curves are the pieces I have no holes, the pieces I have holes of 3 mm diameter, the pieces I have holes of 4 mm diameter and the pieces I have holes of 6 mm diameter) ;
  • Figure 5 is a comparison of three dissolution profiles of a two-layered sheet of the hypnotic agent Example 1 with a sustained release layer having pores (bore diameters of 4 mm, 6 mm) and a sustained release layer without pores;
  • Figure 6 is a three dissolution curve of the hypnotic agent Example 2 sustained-release layer porous (pore size 4 mm, 6 mm) and the sustained-release layer non-porous two-layer sheet, and the dissolution curve of the individual immediate release layer;
  • Figure 7 is a comparison of three dissolution profiles of the hypnotic agent Example 3 sustained-release layer with pores (bore pore diameters of 4 mm, 6 mm) and a sustained-release layer non-porous two-layer sheet;
  • Fig. 8 is a comparison of two dissolution profiles of a two-layered sheet of the hypnotic agent Example 4 sustained-release layer with pores (bore diameters of 4 mm, 6 mm, respectively).
  • Figure 9 is an in vitro release profile of the double-layer controlled release tablet of Example 1 of analgesic
  • Figure 10 is an in vitro release profile of the double-layer controlled release tablet of the analgesic Example 2;
  • Figure 11 is a dissolution profile of the double-layer controlled release tablet of the analgesic Example 3.
  • Examples 1-5 The double-layer controlled release tablets of Examples 1-5 consisted of an immediate release layer and a sustained release layer. The two layers of the particles used to compress the two-layer sheet are shown in Table 1 below:
  • the above two-layer sheet may be coated, and the coating layer contains the following components:
  • a sustained release granule is obtained for forming a sustained release layer.
  • the present embodiment firstly prepared a sustained-release laminate into a sustained-release sheet with no pores, a hole of 3 mm, a hole of 4 mm, and a pore size of 6 mm, and was subjected to a dissolution test. Large, the faster the dissolution rate.
  • the prepared two-layer tablet was subjected to dissolution test to investigate the effect of sustained release of the tablet immediately after immediate release.
  • the sample was detected by 0.5 h, and the immediate release layer was completely dissolved.
  • the results are shown in Fig. 9.
  • the release of the sustained-release layer exhibits a zero-order release effect, that is, the release of the drug is approximately constant, and the constant release in vitro helps to maintain a stable blood concentration in the body. It is worth mentioning that the release rate of the sustained release layer is large.
  • a sustained release granule is obtained for forming a sustained release layer.
  • An immediate release granule is obtained for forming an immediate release layer and a pore for filling the sustained release layer.
  • sustained release layer particles are added with the remaining silica and magnesium stearate to form a sustained release sheet with a hole in the middle, the pore diameter is 4 mm, 6 mm;
  • the disintegration rate of the two-layer immediate release layer was investigated, and the effect of the sustained release of the two-layered film was as follows. After 0.25 h sampling, the release of the immediate release layer exceeded 85%. The results are shown in Fig. 10.
  • the release of the sustained-release layer exhibits a zero-order release effect, that is, the release of the drug is approximately constant, and the constant release in vitro helps to maintain a stable blood concentration in the body. It is worth mentioning that the release rate of the sustained release layer is large.
  • a sustained release granule is obtained for forming a sustained release layer.
  • sustained release layer particles are added with the remaining silica and magnesium stearate to form a sustained release sheet with a hole in the middle, the pore diameter is 4 mm, 6 mm;
  • the prepared two-layer tablet was subjected to dissolution test to investigate the effect of sustained release of the tablet immediately after release, and the dissolution curve showed that the immediate release and sustained release effects were remarkable, and the results are shown in FIG.
  • a sustained release granule is obtained for forming a sustained release layer.
  • An immediate release granule is obtained for forming an immediate release layer and a pore for filling the sustained release layer.
  • sustained release layer particles are added with the remaining silica and magnesium stearate to form a sustained release sheet with a hole in the middle, the pore diameter is 4 mm, 6 mm;
  • the preparation method was the same as that of Example 3 except that the ingredients used were different, as shown in Table 1.
  • the inventors respectively selected the sustained-release layer without pores, and the sustained-release layer respectively had a double-layered sheet of 3 mm, 4 mm or 6 mm holes (the composition and ratio of the original excipients were exactly the same as in Example 1, all the experimental pieces were identical).
  • the friability test was used to conduct a comparative study of the friability test. The results are shown in Table 2:
  • the pore size has a positive effect on preventing delamination, but when the pore size is large, it affects the damage of the double layer.
  • the prescription release layer contained super disintegrant
  • the disintegration agent had strong hygroscopicity, but the environmental humidity was large, the immediate release layer was more swollen than the slow release layer, and the double layer piece was easy to be separated.
  • the stability of the two-layer sheet of the present invention is still good, and no delamination occurs.
  • Example 3 According to the formulation of Example 3 (the immediate release layer contains only the active ingredient and the excipient, no binder), the sustained release layer has no pores, and the sustained release layer has one, two and three pores respectively.
  • the layers were taken, 20 pieces each, and the friability test in the friability tester was carried out for comparative study. The results are shown in Table 4:
  • the formulation of the double-layer controlled release tablet coating of the sleeping pills Examples 1-5 is the same as the aforementioned sleeping agent examples.
  • the prepared soft material is granulated with a 24-mesh sieve
  • a sustained release granule is obtained for forming a sustained release layer.
  • the prepared soft material is granulated with a 24-mesh sieve
  • An immediate release granule is obtained for forming an immediate release layer and a pore for filling the sustained release layer.
  • sustained release granules are added with the remaining silica and magnesium stearate to form a sustained release layer with an intermediate pore size of 3 mm, 4 mm, and 6 mm, respectively; and a sustained release layer having no pores is also pressed;
  • the sustained release tablet is placed in the die of the tableting machine, the immediate release granules are filled, and the second pressing is performed with a shallow concave punch to form a double layer sheet;
  • the present embodiment firstly prepared a sustained-release laminate into a sustained-release sheet with no pores, a hole of 3 mm, a hole of 4 mm, and a pore size of 6 mm, and was subjected to a dissolution test. Large, the faster the dissolution rate.
  • the results are shown in Figure 4.
  • the prepared two-layer tablet was subjected to a dissolution test to investigate the effect of sustained release of the tablet immediately after immediate release, and the immediate release layer was completely dissolved after 0.5 h sampling.
  • the results are shown in Fig. 5. It can be seen from the figure that the sustained release layer has pores for achieving a constant rate of release.
  • the prepared soft material is granulated with a 24-mesh sieve
  • a sustained release granule is obtained for forming a sustained release layer.
  • the prepared soft material is granulated with a 24-mesh sieve
  • sustained release granules and the remaining silica and magnesium stearate are pressed into a sustained release layer with a hole in the middle, the pore diameter is 4 mm, 6 mm;
  • a sustained release granule is obtained for forming a sustained release layer.
  • the prepared soft material is granulated with a 24-mesh sieve
  • An immediate release granule is obtained for forming an immediate release layer and a pore for filling the sustained release layer.
  • sustained release granules and the remaining silica and magnesium stearate are pressed into a sustained release layer with a hole in the middle, the pore diameter is 4 mm, 6 mm;
  • the prepared two-layer tablet was subjected to dissolution test to investigate the effect of sustained release of the tablet immediately after immediate release.
  • the sample was detected by 0.5 h, and the immediate release layer was completely dissolved.
  • the results are shown in Fig. 7.
  • a sustained release granule is obtained for forming a sustained release layer.
  • the prescription immediate release layer contains a super disintegrant, and the disintegrating agent has strong hygroscopicity.
  • the immediate release layer expands more than the sustained release layer, and the upper and lower layers of the double layer without pores are easily separated.
  • the sustained release layer has pores, the immediate release particles in the pores absorb moisture and expand, and the immediate release layer is more closely bonded to the sustained release layer. Therefore, the two-layer sheet with holes in the experiment did not separate.
  • the sustained release layer has no pores and a sustained release layer having a different number of pores, and the immediate release layer contains only the active ingredient and the excipient, and the double layer sheet containing no binder 20 pieces were compared in the friability tester for the friability test.
  • Table 8 The results are shown in Table 8:
  • the double-layer sheet with a large number of holes is less likely to be damaged.
  • the two-layer sheet prepared by the invention has better physical stability than the ordinary two-layer sheet, is more convenient for storage and transportation, and the drug release is approximately constant speed.

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Abstract

一种双层片，其中一层药片具有孔，孔中具有另一层药片的成分。所述孔的数量是1-3个，孔的直径为1∼10mm。双层中每一层均包括活性成分和/或辅料，每一层均可以分别是速释层或缓释层；制备方法是：分别制备含有活性成分和药用辅料的成分I、成分Ⅱ；将成分I制成带有孔的片I，然后将成分Ⅱ和片I一起压制，形成双层片，且成分Ⅱ在压制过程中将充入片Ⅰ的孔中。实验证实，本发明的双层片物理稳定性高，在运输和贮存过程中不易破裂，且药物释放近似恒速，有助于实现药物在体内保持平稳血药浓度，极大的提高了患者服药的有效性和安全性。

Description

一种双层片及其制备方法
本申请针对以下三项中国专利申请提出优先权请求：
申请号为201310717968.1名称为“一种双层片的制备方法”
申请号为201310716482.6名称为“一种止痛类双层控释片及其制备方法”
申请号为201310718529.2名称为“一种安眠类双层控释片及其制备方法”
以上三项在先申请的申请日均为20131223。
技术领域
本发明涉及药物制剂领域，具体涉及一种新型的双层片及其制备方法。
背景技术
双层片是一种含有双层结构的双相释药系统，它不仅可以将两种药物或同一种药物以不同释放模式组合在一起达到理想的药动学行为，而且能提高有配伍反应药物的稳定性，还能赋予片剂特殊的功能。
在双层片的制备中，保证双层片药品在货架期结构稳定是制药工业最具需求和实用的技术。
现有技术的双层片的结构是两层片上下贴合在一起，其制备方法通常是两层片分次压制。比如，先将双层片中其中一层的药物活性成分和辅料混合，压制成一层药片，再将该层药片与另一层药片的药物活性成分和辅料一起压制成双层片。
现有技术双层片的缺点是物理稳定性差，容易发生碎裂和两层片的分离。这是因为通常两层药片所用的辅料往往不同，而不同辅料的膨胀系数会有差别，导致制剂在运输和贮存过程中发生药片裂开等情况。
因此，提高双层片的物理稳定性，保证在运输和贮存过程中制剂的完整，很有必要。
发明内容
本发明的目的是提供一种物理稳定性高，在运输和贮存过程中不易破裂,且药物释放近似恒速，提高患者服药的有效性和安全性的双层片。
本发明通过设计了一种新结构的双层片，达到了上述发明目的。其技术方案是：
一种双层片，为双层释药模式，由两层药片结合而成，其特征是：其中一层药片具有孔。当制成制剂后，所述孔中具有另一层药片的成分。
上述双层片中每一层均包括活性成分和辅料，其中每一层中的活性成分可以是一种，也可以是两种及以上活性成分的复方。
双层中两层的活性成分可以相同，也可以不同；
两层药片中每一层均可以分别是速释层或缓释层；
所述孔的数量是1-3个，优选是1个。
所述孔的直径为1～10mm，优选为2-6mm。
所述双层片还可以根据实际需要，按本领域常规方法进行包衣等处理。
上述双层片的制备方法是：
1)分别制备含有活性成分和药用辅料的成分I、成分Ⅱ；
所述成分I、成分Ⅱ是颗粒状或粉末状；
2)第一次压片：将成分I制成带有孔的片状物(以下亦称为片I)；
第二次压片：将成分Ⅱ和上述片状物一起压制，形成由成分I层和成分Ⅱ层组成的双层片，成分Ⅱ在压制过程中充入片状物的孔中。
片Ⅰ中所述的孔的形成方法是用带有孔的模型压制，或者也可以压片后打孔；在本发明的一个实例中，成分I是经环形冲头压制成有孔的片Ⅰ。
本发明的优点在于双层片的成分I层为有孔的，由于片Ⅰ的孔中充填成分Ⅱ，这样得到的双层片非常牢固，在储存和运输过程中不易分离。其结构见图1～3。
本发明的双层片制备方法适合于各类双层片的制备。本领域技术人员可根据实际需要选择各种常规的药用辅料。
药用辅料优选自缓释材料、填充剂、崩解剂、润滑剂、粘合剂、助流剂中的一种或几种。
其中缓释材料优选自羟丙甲基纤维素、乙基纤维素、羟丙基纤维素的一种或几种；填充剂优选自乳糖、预交化淀粉、微晶纤维素的一种或几种；崩解剂优选自羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮中的一种或几种；润滑剂优选自硬脂酸、硬脂酸镁、滑石粉的一种或几种；粘合剂优选自聚维酮、羟丙基纤维素、羟丙甲基纤维素的一种或多种；助流剂优选微粉硅胶。
本发明中成分I中各组分所占的重量百分比优选为：
Figure PCTCN2014094367-appb-000001
Figure PCTCN2014094367-appb-000002
本发明中Ⅱ颗粒中各组分所占的重量百分比优选为：
Figure PCTCN2014094367-appb-000003
本发明的双层片还优选包衣，其中包衣层优选含有下列组分及百分比：
Figure PCTCN2014094367-appb-000004
以下是按本发明的方案制备的一个止痛类速释/缓释相结合的双层片实例：
一种止痛类双层控释片，包括速释层和缓释层，所述速释层和缓释层中均含有止痛作用的活性成分及药物辅料，其特征是，所述缓释层有孔，孔中填充有速释层药物的颗粒，孔的直径为2-6mm。
所述有止痛作用的活性成分选自阿司匹林、水杨酸镁、水杨酸钠、水杨酸胆碱镁、二氟尼柳、双水杨酸酯、布洛芬、吲哚美辛、氟比洛芬、苯氧基布洛芬、萘普生、萘丁美酮、吡罗昔康、保泰松、双氯灭痛、芬洛芬、酮基布洛芬、酮咯酸、四氯芬那酸、舒林酸、托美丁或山莨菪碱，或者上述化合物的衍生物中的一种或几种；
所述速释层和缓释层所含的活性成分可以相同或不同；
所述药用辅料选自填充剂、崩解剂、润滑剂、粘合剂、助流剂中的一种或几种；
以下列举的各类辅料可以选用，但不限定本发明的范围。实际上，本发明所用的各种药用辅料可以根据实际需求，选择本领域技术人员常用的各种辅料。比如，
所述填充剂选自一水乳糖、乳糖、预交化淀粉和微晶纤维素中的一种或几种；
所述崩解剂选自羧甲基纤维素钠、交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚维酮中的一种或几种；
所述润滑剂选自硬脂酸、硬脂酸镁和滑石粉中的一种或几种；
所述粘合剂选自聚维酮、羟丙基纤维素和羟丙甲基纤维素中的一种或多种；
所述助流剂为二氧化硅。
此外，止痛类双层片中的缓释层还含有缓释材料。
所述的缓释材料选自羟丙甲基纤维素、乙基纤维素、羟丙基纤维素的一种或几种；所述的
所述的缓释层中，按照重量百分比包括以下组分：
Figure PCTCN2014094367-appb-000005
所述的速释层和速释颗粒中，按照重量百分比包括以下组分：
Figure PCTCN2014094367-appb-000006
所述的双层控释片还包括包衣层，所述的包衣层按照重量百分比包括以下组分：
Figure PCTCN2014094367-appb-000007
止痛类双层控释片的制备方法，其特征在于，包括以下步骤：
1)将止痛类药物与缓释材料和药用辅料混合制成缓释颗粒；将止痛类药物与药用辅料混合制成速释颗粒；
2)将缓释颗粒压制成有孔的缓释层，再将缓释层重新放入压片机的冲模中，装填速释颗粒，进行第二次压制，形成由速释层和缓释层组成的双层片，其中缓释层的孔中填充有速释颗粒。
3)进行包衣。
以下是按本发明的方案制备的一个安眠类速释/缓释相结合的双层片实例：
所述的安眠类药物选自唑吡坦、扎来普隆、佐匹克隆、三唑仑、咪达唑仑、氟西泮、地西泮、氯氮卓、硝西泮、艾司唑仑、阿普唑仑或劳拉西泮，或者上述化合物的衍生物中的一 种；所述的缓释材料选自羟丙甲基纤维素、乙基纤维素或羟丙基纤维素中的一种或几种；所述的药用辅料选自填充剂、崩解剂、润滑剂、粘合剂、助流剂中的一种或几种。
所述的填充剂选自一水乳糖、乳糖、预交化淀粉和微晶纤维素的一种或几种；所述的崩解剂选自羧甲基纤维素钠、交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚维酮中的一种或几种；所述的润滑剂选自硬脂酸、硬脂酸镁和滑石粉的一种或几种；所述的粘合剂选自聚维酮、羟丙基纤维素和羟丙甲基纤维素的一种或多种；所述的助流剂为二氧化硅。
所述的的双层控释片中，所述的缓释层中，按照重量百分比包括以下组分：
Figure PCTCN2014094367-appb-000008
所述的速释层和速释颗粒中，按照重量百分比包括以下组分：
Figure PCTCN2014094367-appb-000009
上述安眠类双层控释片的制备方法包括以下步骤：
1)将安眠类药物与缓释材料和药用辅料混合制成缓释颗粒；将安眠类药物与药用辅料混合制成速释颗粒；
2)将缓释颗粒压制成有孔的缓释层，再将缓释层重新放入压片机的冲模中，装填速释颗粒，进行第二次压制，形成由速释层和缓释层组成的双层片，其中缓释层的孔中填充有速释颗粒。
3)进行包衣，包衣层的配方和制备方法同前述止痛类双层控释片。
本发明具有如下技术效果：
1)物理稳定性好
由于双层片中其中一层有孔，在制片过程中，该孔被另一层的成分所填充，使双层片结合紧密，在储存和运输过程中不易分离。
2)提高了药物的有效性和安全性
本双层控释片经溶出试验检测速释层崩解时限为10～30秒，缓释层呈零级释放模式，即 药物释放近似恒速，有助于实现药物在体内保持平稳血药浓度，极大的提高了患者服药的有效性和安全性。
附图说明
图1是带有一个孔的双层片的结构示意图；
图2是带有二个孔的双层片的结构示意图；
图3是带有三个孔的双层片的结构示意图；
图1-图3中，1是片I，2是片II，3是孔；
图4是安眠药实施例1双层片溶出曲线(其中四条曲线分别为是片I无孔，片I带有3mm直径的孔，片I带有4mm直径的孔和片I带有6mm直径孔)；
图5是安眠药实施例1缓释层有孔(孔径分别为4mm、6mm)和缓释层无孔的双层片的三条溶出曲线比较；
图6是安眠药实施例2缓释层有孔(孔径分别为4mm、6mm)和缓释层无孔的双层片的三条溶出曲线，以及单独速释层的溶出曲线比较；
图7是安眠药实施例3缓释层有孔(孔径分别为4mm、6mm)和缓释层无孔的双层片的三条溶出曲线比较；
图8是安眠药实施例4缓释层有孔(孔径分别为4mm、6mm)的双层片的两条溶出曲线比较。
图9是止痛药实施例1双层控释片体外释放曲线；
图10是止痛药实施例2双层控释片片体外释放曲线；
图11是止痛药实施例3双层控释片的溶出曲线；
图12止痛药实施例4双层控释片的溶出曲线。
具体实施方式
止痛药实施例1-5的双层控释片由速释层和缓释层组成，用于压制双层片的两层的颗料分别见如下表1：
表1
各实施例的双层控释片的处方(1000片，g)
Figure PCTCN2014094367-appb-000010
上述双层片可用包衣，包衣层含如下组分：
羟丙甲基纤维素E5 30
聚山梨醇酯80 14
滑石粉 5
二氧化钛 2
80％醇/水溶液 适量
止痛药实施例1-5的双层控释片制备方法见如下。
止痛药实施例1
1、制备缓释颗粒：
(1)称量处方量的已过60目筛的布洛芬与羟丙甲基纤维素K100LV，K4M，乳糖充分混合，之后加入处方量二分之一的二氧化硅和硬脂酸镁。将混合好的物料转移至湿法制粒机中；
(2)配制浓度为70％的乙醇溶液对步骤1中的混合物进行制软材；
(3)将制好的软材用24目筛进行整粒；
(4)干燥并筛分颗粒
(5)得到缓释颗粒，用于形成缓释层。
2、制备速释颗粒：
(1)将处方量的酮洛芬，乳糖，微晶纤维素，聚维酮混合过60目筛，加入处方量一半的二氧化硅和硬脂酸镁，在混料机中混合均匀；
(2)配制浓度为80％的乙醇溶液对步骤1中的混合物进行制软材；
(3)将制好的软材用24目筛进行整粒；
(4)干燥并筛粉颗粒；
(5)按照外加法添加交联羧甲基纤维素钠与干颗粒混合均匀；
(6)得到速释颗粒，用于形成速释层和用于填充缓释层的孔。
3、制备双层控释片：
(1)将缓释层颗粒加剩余的二氧化硅和硬脂酸镁压制成中间有孔的缓释片，孔径分别为3mm，4mm，6mm；另外还压制了没有孔的缓释片；
(2)将缓释片重新放入压片机的冲模中，装填速释层颗粒，用浅凹冲进行第二次压制，形成双层片；
(3)将处方量的羟丙基甲基纤维素E 5分散在浓度为80％乙醇中，溶胀后加入聚山梨醇酯80，搅拌溶解完全，再加入二氧化钛和滑石粉，搅拌均匀，过滤后作为包衣液；
(4)将双层片包衣，使每片增重5％，再干燥固化。
为了考察缓释层孔径对溶出的影响，本实施例先将缓释层压制成为不带孔、带3mm孔、带4mm孔、带6mm孔径的缓释片，进行溶出实验，缓释层孔径越大，溶出速度越快。
将制备好的双层片进行溶出实验，考察药片先速释后缓释的效果，0.5h取样检测，速释层已完全溶出，结果见图9。缓释层溶出呈现零级释放效果，即药物释放近似恒速，体外恒速释放有助于实现药物在体内保持平稳血药浓度，值得一提的是，缓释层孔径大的释放速度快。
止痛药实施例2
1、制备缓释颗粒：
(1)称量处方量的已过60目筛的布洛芬与羟丙甲基纤维素K100LV，K4M，乳糖充分混合，之后加入处方量二分之一的二氧化硅和硬脂酸镁。将混合好的物料转移至湿法制粒机中；
(2)配制浓度为75％的乙醇溶液对步骤1中的混合物进行制软材；
(3)将制好的软材用24目筛进行整粒；
(4)干燥并筛分颗粒
(5)得到缓释颗粒，用于形成缓释层。
2、制备速释颗粒：
(1)将处方量的萘普生，乳糖，微晶纤维素和羟丙基纤维素-HF，羧甲基纤维素钠混合过60目筛，加入处方量一半的二氧化硅和硬脂酸镁，在混料机中混合均匀；
(2)配制浓度为90％的乙醇溶液对步骤1中的混合物进行制软材；
(3)将制好的软材用24目筛进行整粒；
(4)干燥并筛粉颗粒
(5)得到速释颗粒，用于形成速释层和用于填充缓释层的孔。
3、制备双层控释片：
(1)将缓释层颗粒加剩余的二氧化硅和硬脂酸镁压制成中间有孔的缓释片，孔径分别为4mm，6mm；
(2)将缓释片重新放入压片机的冲模中，装填速释层颗粒，用浅凹冲进行第二次压制，形成双层片；
(3)将处方量的羟丙基甲基纤维素E 5分散在浓度为80％乙醇中，溶胀后加入聚山梨醇酯80，搅拌溶解完全，再加入二氧化钛和滑石粉，搅拌均匀，过滤后作为包衣液；
(4)将双层片包衣，使每片增重5％，再干燥固化。
考察双层片速释层崩解速度，和双层片先速释后缓释的效果，0.25h取样检测，速释层溶出超过85％，结果见图10。缓释层溶出呈现零级释放效果，即药物释放近似恒速，体外恒速释放有助于实现药物在体内保持平稳血药浓度，值得一提的是，缓释层孔径大的释放速度快。
止痛药实施例3
1、制备缓释颗粒：
(1)称量处方量的已过60目筛的萘普生与羟丙甲基纤维素K100LV，K4M，乳糖充分混合，之后加入处方量二分之一的二氧化硅和硬脂酸镁。将混合好的物料转移至湿法制粒机中；
(2)配制浓度为80％的乙醇溶液对步骤1中的混合物进行制软材；
(3)将制好的软材用24目筛进行整粒；
(4)干燥并筛分颗粒
(5)得到缓释颗粒，用于形成缓释层。
2、制备速释颗粒：
(1)将处方量的萘普生，乳糖，微晶纤维素和羟丙基纤维素-HF，羧甲基纤维素钠混合过60目筛，加入处方量一半的二氧化硅和硬脂酸镁，在混料机中混合均匀；
(2)配制浓度为90％的乙醇溶液对步骤1中的混合物进行制软材；
(3)将制好的软材用24目筛进行整粒；
(4)干燥并筛粉颗粒
(5)得到速释颗粒，用于形成速释层和用于填充缓释层的孔。
3、制备双层控释片：
(1)将缓释层颗粒加剩余的二氧化硅和硬脂酸镁压制成中间有孔的缓释片，孔径分别为4mm，6mm；
(2)将缓释片重新放入压片机的冲模中，装填速释层颗粒，用浅凹冲进行第二次压制，形成双层片；
(3)将处方量的羟丙基甲基纤维素E 5分散在浓度为80％乙醇中，溶胀后加入聚山梨醇酯80，搅拌溶解完全，再加入二氧化钛和滑石粉，搅拌均匀，过滤后作为包衣液；
(4)将双层片包衣，使每片增重5％，再干燥固化。
将制备好的双层片进行溶出实验，考察药片先速释后缓释的效果，由溶出曲线可以看出速释和缓释效果明显，结果见图11。
止痛药实施例4
1、制备缓释颗粒：
(1)称量处方量的已过60目筛的布洛芬与羟丙甲基纤维素K100LV，K4M，乳糖充分混合，之后加入处方量二分之一的二氧化硅和硬脂酸镁。将混合好的物料转移至湿法制粒机中；
(2)配制浓度为80％的乙醇溶液对步骤1中的混合物进行制软材；
(3)将制好的软材用24目筛进行整粒；
(4)干燥并筛分颗粒
(5)得到缓释颗粒，用于形成缓释层。
2、制备速释颗粒：
(1)将处方量的布洛芬，乳糖，微晶纤维素和羟丙基纤维素-HF，羧甲基纤维素钠混合过60目筛，加入处方量一半的二氧化硅和硬脂酸镁，在混料机中混合均匀；
(2)配制浓度为90％的乙醇溶液对步骤1中的混合物进行制软材；
(3)将制好的软材用24目筛进行整粒；
(4)干燥并筛粉颗粒
(5)得到速释颗粒，用于形成速释层和用于填充缓释层的孔。
3、制备双层控释片：
(1)将缓释层颗粒加剩余的二氧化硅和硬脂酸镁压制成中间有孔的缓释片，孔径分别为4mm，6mm；
(2)将缓释片重新放入压片机的冲模中，装填速释层颗粒，用浅凹冲进行第二次压制，形成双层片；
(3)将处方量的羟丙基甲基纤维素E 5分散在浓度为80％乙醇中，溶胀后加入聚山梨醇酯 80，搅拌溶解完全，再加入二氧化钛和滑石粉，搅拌均匀，过滤后作为包衣液；
(4)将双层片包衣，使每片增重5％，再干燥固化。
制备单层速释片和双层片进行溶出实验，考察药片速释层崩解速度，缓释层孔径对缓释效果的影响，0.5h取样检测，速释层溶出超过90％；在这个实施例中缓释层体外溶出曲线的线性效果4mm孔径优于6mm孔径，结果见图12。
止痛药实施例5
制备方法同实施例3，但所用成分不同，见表1。
以下是本发明止痛双层片的稳定性实验：
实验1 脆碎度实验
发明人分别选了缓释层没有孔，及缓释层分别有一个3mm、4mm或6mm孔的双层片各100片(原辅料组成和配比按实施例1，所有实验片完全一致)，使用脆碎度检测仪分别进行脆碎度实验对比研究，结果如表2：
表2 双层片脆碎度实验对比结果
Figure PCTCN2014094367-appb-000011
从上述脆碎度实验结果可证实：
1)本发明有孔的双层片破损片的发生率极大地降低，且不发生分层；
2)孔径大小对防止分层均有积极作用，但孔径大时，影响双层片破损度。
试验2 高湿对药物稳定度的影响
从实施例4中选了双层片各20片，放置于稳定性试验箱中，湿度设定为RH95％，温度设为25℃，放置24h后观察，结果如下表3：
表3 高湿对药物稳定度的影响
Figure PCTCN2014094367-appb-000012
Figure PCTCN2014094367-appb-000013
结果表明：虽然该处方速释层中含有超级崩解剂，崩解剂的吸湿性较强，但是在环境湿度较大，速释层比缓释层膨胀程度大，双层片易分离的情况下，本发明的双层片稳定性仍很好，没有分层出现。
试验3 双层片中孔的数量对稳定性的影响
按照实施例3的配方(速释层中仅含有活性成分和赋形剂，不含有粘合剂)压制了缓释层没有孔，及缓释层分别有一个、两个和三个孔的双层片，各取20片，在脆碎度检测仪中分别脆碎度实验进行对比研究，结果如表4：
表4 孔的数量对稳定性的影响对比
Figure PCTCN2014094367-appb-000014
从上述脆碎度实验可证实：
1、有孔的双层片破损片的发生率极大地降低，且不发生分层；
2、孔的数量增大时，破损片更少。
安眠药实施例1-5的双层控释片的处方如下表5：
表5
Figure PCTCN2014094367-appb-000015
安眠药实施例1-5的双层控释片包衣的配方同前述安眠药实施例。
制备方法分别如下：
安眠药实施例1
1、制备缓释颗粒：
①称量处方量的已过60目筛的酒石酸唑吡坦与羟丙甲基纤维素K100LV，K4M，一水乳糖充分混合，之后加入处方量二分之一的二氧化硅和硬脂酸镁。将混合好的物料转移至湿法制粒机中；
②配制浓度为70％的乙醇溶液对步骤1中的混合物进行制软材；
③将制好的软材用24目筛进行整粒；
④干燥并筛分颗粒；
⑤得到缓释颗粒，用于形成缓释层。
2、制备速释颗粒：
①将处方量的酒石酸唑吡坦，乳糖，微晶纤维素，聚维酮混合过60目筛，加入处方量一半的二氧化硅和硬脂酸镁，在混料机中混合均匀；
②配制浓度为80％的乙醇溶液对步骤1中的混合物进行制软材；
③将制好的软材用24目筛进行整粒；
④干燥并筛粉颗粒；
⑤按照外加法添加交联羧甲基纤维素钠与干颗粒混合均匀；
⑥得到速释颗粒，用于形成速释层和用于填充缓释层的孔。
3、制备双层控释片：
①将缓释颗粒加剩余的二氧化硅和硬脂酸镁压制成中间有孔的缓释层，孔径分别为3mm，4mm，6mm；另外还压制了没有孔的缓释层；
②将缓释片重新放入压片机的冲模中，装填速释颗粒，用浅凹冲进行第二次压制，形成双层片；
③将处方量的羟丙基甲基纤维素E 5分散在浓度为80％乙醇中，溶胀后加入聚山梨醇酯80，搅拌溶解完全，再加入二氧化钛和滑石粉，搅拌均匀，过滤后作为包衣液；
④将双层片包衣，使每片增重5％，再干燥固化。
为了考察缓释层孔径对溶出的影响，本实施例先将缓释层压制成为不带孔、带3mm孔、带4mm孔、带6mm孔径的缓释片，进行溶出实验，缓释层孔径越大，溶出速度越快。结果见图4。将制备好的双层片进行溶出实验，考察药片先速释后缓释的效果，0.5h取样检测，速释层已完全溶出，结果见图5。从图可看出，缓释层有孔可以实现恒速释放的作用。
安眠药实施例2
1、制备缓释颗粒：
①称量处方量的已过60目筛的酒石酸唑吡坦与羟丙甲基纤维素K100LV，K4M，乳糖充分混合，之后加入处方量二分之一的二氧化硅和硬脂酸镁。将混合好的物料转移至湿法制粒机中；
②配制浓度为75％的乙醇溶液对步骤1中的混合物进行制软材；
③将制好的软材用24目筛进行整粒；
④干燥并筛分颗粒；
⑤得到缓释颗粒，用于形成缓释层。
2、制备速释颗粒：
①将处方量的酒石酸唑吡坦，乳糖，微晶纤维素和羟丙基纤维素-HF，羧甲基纤维素钠混合过60目筛，加入处方量一半的二氧化硅和硬脂酸镁，在混料机中混合均匀；
②配制浓度为90％的乙醇溶液对步骤1中的混合物进行制软材；
③将制好的软材用24目筛进行整粒；
④干燥并筛粉颗粒；
⑤得到速释颗粒，用于形成速释层和用于填充缓释层的孔。
3、制备双层控释片：
①将缓释颗粒加剩余的二氧化硅和硬脂酸镁压制成中间有孔的缓释层，孔径分别为4mm，6mm；
②将缓释层重新放入压片机的冲模中，装填速释颗粒，用浅凹冲进行第二次压制，形成双层片；
③将处方量的羟丙基甲基纤维素E 5分散在浓度为80％乙醇中，溶胀后加入聚山梨醇酯80，搅拌溶解完全，再加入二氧化钛和滑石粉，搅拌均匀，过滤后作为包衣液；
④将双层片包衣，使每片增重5％，再干燥固化。
制备单层速释片和双层片进行溶出实验，考察药片速释层崩解速度，和双层片先速释后缓释的效果，0.25h取样检测，速释层溶出超过90％，结果见图6。
安眠药实施例3
1、制备缓释颗粒：
①称量处方量的已过60目筛的佐匹克隆与羟丙甲基纤维素K100LV，K4M，乳糖充分混合，之后加入处方量二分之一的二氧化硅和硬脂酸镁。将混合好的物料转移至湿法制粒机中；
②配制浓度为80％的乙醇溶液对步骤1中的混合物进行制软材；
③将制好的软材用24目筛进行整粒；
④干燥并筛分颗粒；
⑤得到缓释颗粒，用于形成缓释层。
2、制备速释颗粒：
①将处方量的佐匹克隆，乳糖，微晶纤维素和羟丙基纤维素-HF，羧甲基纤维素钠混合过60目筛，加入处方量一半的二氧化硅和硬脂酸镁，在混料机中混合均匀；
②配制浓度为90％的乙醇溶液对步骤1中的混合物进行制软材；
③将制好的软材用24目筛进行整粒；
④干燥并筛粉颗粒；
⑤得到速释颗粒，用于形成速释层和用于填充缓释层的孔。
3、制备双层控释片：
①将缓释颗粒加剩余的二氧化硅和硬脂酸镁压制成中间有孔的缓释层，孔径分别为4mm，6mm；
②将缓释层重新放入压片机的冲模中，装填速释颗粒，用浅凹冲进行第二次压制，形成双层片；
③将处方量的羟丙基甲基纤维素E 5分散在浓度为80％乙醇中，溶胀后加入聚山梨醇酯80，搅拌溶解完全，再加入二氧化钛和滑石粉，搅拌均匀，过滤后作为包衣液；
④将双层片包衣，使每片增重5％，再干燥固化。
将制备好的双层片进行溶出实验，考察药片先速释后缓释的效果，0.5h取样检测，速释层已完全溶出，结果见图7。
安眠药实施例4
1、制备缓释颗粒：
①称量处方量的已过60目筛的扎来普隆与羟丙甲基纤维素K100LV，K4M，乳糖充分混合，之后加入处方量二分之一的二氧化硅和硬脂酸镁。将混合好的物料转移至湿法制粒机中；
②配制浓度为80％的乙醇溶液对步骤1中的混合物进行制软材；
③将制好的软材用24目筛进行整粒；
④干燥并筛分颗粒；
⑤得到缓释颗粒，用于形成缓释层。
2、制备速释颗粒：
①将处方量的扎来普隆，乳糖，微晶纤维素和羟丙基纤维素-HF，羧甲基纤维素钠混合过60目筛，加入处方量一半的二氧化硅和硬脂酸镁，在混料机中混合均匀；
②配制浓度为90％的乙醇溶液对步骤1中的混合物进行制软材；
③将制好的软材用24目筛进行整粒；
④干燥并筛粉颗粒；
⑤得到速释颗粒，用于形成速释层和用于填充缓释层的孔。
3、制备双层控释片：
①将缓释颗粒加剩余的二氧化硅和硬脂酸镁压制成中间有孔的缓释层，孔径分别为4mm，6mm；
②将缓释层重新放入压片机的冲模中，装填速释颗粒，用浅凹冲进行第二次压制，形成双层片；
③将处方量的羟丙基甲基纤维素E 5分散在浓度为80％乙醇中，溶胀后加入聚山梨醇酯80，搅拌溶解完全，再加入二氧化钛和滑石粉，搅拌均匀，过滤后作为包衣液；
④将双层片包衣，使每片增重5％，再干燥固化。
制备单层速释片和双层片进行溶出实验，考察药片速释层崩解速度，和双层片先速释后缓释的效果，0.25h取样检测，速释层溶出超过90％，结果见图8。
安眠药实施例5
制备方法同实施例3，但所用成分不同，见表1。
安眠药的脆碎度实验和稳定性实验
按照实施例1的配方和方法，制备了缓释层没有孔和缓释层孔径不同的双层片各100片，在脆碎度检测仪中分别进行脆碎度实验对比研究，结果如表6：
表6
Figure PCTCN2014094367-appb-000016
结果表明：
1、缓释层有孔的双层片均无片层分离的现象；
2、孔径小的更不易破损。
按照实施例4的配方和方法，制备了缓释层没有孔和缓释层孔径不同的双层片各20放置于稳定性试验箱中，湿度设定为RH95％，温度设为25℃。
放置24h后观察，结果如下表7：
表7
Figure PCTCN2014094367-appb-000017
该处方速释层中含有超级崩解剂，崩解剂的吸湿性较强，当环境湿度较大时，速释层比缓释层膨胀程度大，没有孔的双层片上下层易分离。当缓释层带有孔后，孔中的速释颗粒吸湿膨胀，速释层与缓释层接合更紧密。故实验过程中带有孔的双层片均无分离现象。
结果表明：本发明的双层片在高温高湿环境下仍保持稳定性。
按照实施例3的配方和方法，制备了缓释层没有孔和缓释层有数量不同的孔，且速释层中仅含有活性成分和赋形剂，不含有粘合剂的双层片各20片，在脆碎度检测仪中分别进行脆碎度实验对比研究，结果如表8：
表8
Figure PCTCN2014094367-appb-000018
Figure PCTCN2014094367-appb-000019
结果表明：
1、缓释层有孔的双层片均无片层分离的现象；
2、孔数量多的双层片的更不易破损。
从上述结果可以看出，本发明制备的双层片物理稳定性好于普通双层片，更有利于贮存和运输,且药物释放近似恒速。

Claims (10)

  1. 一种双层片，由两层药片结合而成，其特征是：其中一层药片具有孔，所述孔中具有另一层药片的成分。
  2. 权利要求1所述的双层片，所述孔的数量是1-3个；孔的直径为1～10mm。
  3. 权利要求1所述的双层片，其中一层或两层含有活性成分。
  4. 权利要求3所述的双层片，双层片中两层的活性成分相同或不同；且每一层中的活性成分是一种或两种及以上。
  5. 权利要求1所述的双层片，两层药片中每一层是速释层和/或缓释层。
  6. 权利要求1所述的双层片，所述孔的数量是1个，孔的直径为2-6mm。
  7. 权利要求1-6中任一所述的双层片，包括速释层和缓释层，所述速释层和缓释层中均含有活性成分及药物辅料，其中一层制成有孔层，孔中具有另一层的成分。
  8. 权利要求7所述的双层片，所述活性成分是止痛药物或安眠药物；
    所述止痛药物选自阿司匹林、水杨酸镁、水杨酸钠、水杨酸胆碱镁、二氟尼柳、双水杨酸酯、布洛芬、吲哚美辛、氟比洛芬、苯氧基布洛芬、萘普生、萘丁美酮、吡罗昔康、保泰松、双氯灭痛、芬洛芬、酮基布洛芬、酮咯酸、四氯芬那酸、舒林酸、托美丁或山莨菪碱，或者上述化合物的衍生物中的一种或几种；
    所述安眠药物选自唑吡坦、扎来普隆、佐匹克隆、三唑仑、咪达唑仑、氟西泮、地西泮、氯氮卓、硝西泮、艾司唑仑、阿普唑仑或劳拉西泮，或者上述化合物的衍生物中的一种；所述的缓释材料选自羟丙甲基纤维素、乙基纤维素或羟丙基纤维素中的一种或几种；
    所述的药用辅料选自填充剂、崩解剂、润滑剂、粘合剂、助流剂中的一种或几种。
  9. 权利要求1所述双层片的制备方法，包含以下步骤：
    1)分别制备含有活性成分和药用辅料的成分I、成分Ⅱ；
    所述成分I、成分Ⅱ是颗粒状或粉末状；
    2)第一次压片：将成分I制成带有孔的片状物；
    3)第二次压片：将上述有孔的片状物和成分Ⅱ一起压制，形成由成分I层和成分Ⅱ层
    组成的双层片；且成分Ⅱ在压制过程中被充入孔中。
  10. 权利要求9所述的制备方法，步骤2)中，所述孔的形成方法为：或用带有孔的压片模具压制，或压片后打孔。
PCT/CN2014/094367 2013-12-23 2014-12-19 一种双层片及其制备方法 Ceased WO2015096668A1 (zh)

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EP14874251.3A EP3087980B1 (en) 2013-12-23 2014-12-19 Double-layer tablet and preparation method thereof
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DK14874251.3T DK3087980T3 (en) 2013-12-23 2014-12-19 DOUBLE LAYER TABLE AND METHOD OF PRODUCING THEREOF
US16/178,547 US10925836B2 (en) 2013-12-23 2018-11-01 Double-layer tablet and painkiller tablet with same structure
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ES2712129T3 (es) 2019-05-09
EP3087980B1 (en) 2018-12-05
US20190133960A1 (en) 2019-05-09
US10137092B2 (en) 2018-11-27
US20190133959A1 (en) 2019-05-09
US20160317449A1 (en) 2016-11-03
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US10940114B2 (en) 2021-03-09
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