WO2015154656A1 - 部分包衣的控释固体制剂 - Google Patents

部分包衣的控释固体制剂 Download PDF

Info

Publication number
WO2015154656A1
WO2015154656A1 PCT/CN2015/076028 CN2015076028W WO2015154656A1 WO 2015154656 A1 WO2015154656 A1 WO 2015154656A1 CN 2015076028 W CN2015076028 W CN 2015076028W WO 2015154656 A1 WO2015154656 A1 WO 2015154656A1
Authority
WO
WIPO (PCT)
Prior art keywords
core
layer
coating
release
solid preparation
Prior art date
Application number
PCT/CN2015/076028
Other languages
English (en)
French (fr)
Inventor
闻晓光
Original Assignee
闻晓光
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 闻晓光 filed Critical 闻晓光
Priority to US15/302,977 priority Critical patent/US10413514B2/en
Priority to EP15776295.6A priority patent/EP3130334B8/en
Priority to JP2017504225A priority patent/JP7026876B2/ja
Priority to DK15776295.6T priority patent/DK3130334T3/da
Priority to ES15776295T priority patent/ES2939890T3/es
Publication of WO2015154656A1 publication Critical patent/WO2015154656A1/zh

Links

Images

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • 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
    • 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
    • A61K9/2072—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/2806—Coating materials
    • A61K9/2813—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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • 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
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes

Definitions

  • the invention belongs to the technical field of pharmacy and relates to a partially coated controlled release solid preparation.
  • the active drug is often coated by a slow release material.
  • this method sometimes fails to achieve the desired drug release effect.
  • prior art techniques are difficult to achieve if it is desired that the active ingredients of multiple drugs be released at different speeds at different points in time.
  • a preferred mode of drug release would be to achieve different release behaviors by pulsed administration, especially from slow to fast exponential release. Current formulations do not achieve this effect.
  • the invention designs a solid pharmaceutical preparation with a new structure, and the technical scheme is as follows:
  • a controlled release solid preparation comprising an inner core comprising an active drug and an adjuvant, and a coating comprising a coating material and or with or without an active ingredient, characterized in that said A portion of the surface of the inner core is not coated by the coating and is exposed to the surface of the solid preparation.
  • the coating of the formulation of the present invention incompletely covers the inner core, and a portion of the inner core is exposed to the surface of the solid preparation.
  • the exposed portion has no limitation in its location, area and shape. In practical applications, different shapes of each preparation can be designed according to the release requirements of the active ingredients of the specific preparation and facilitating the production of the medicament.
  • the inner core is one or more layers, and may be one or more layers of a sustained release layer, or both an immediate release layer and a sustained release layer.
  • the components of the different layers are released in sequence: first release the outermost layer, then release the outer outer layer, straight At the end, the innermost layer of the inner core is released. In this way, the release sequence and timing of release of different drugs can be controlled.
  • the material of the sustained release layer is selected from the group consisting of sodium alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone or polyethylene oxide.
  • the material of the coating layer is water-soluble or water-insoluble; the water-soluble coating material is selected from one or more of hydroxypropylmethylcellulose and hydroxypropylcellulose;
  • the water-insoluble coating material is selected from one or more of ethyl cellulose, cellulose acetate polymer, and acrylic resin.
  • the coating material may further comprise a water-soluble porogen selected from one or more of povidone, lactose, and sodium chloride.
  • the inner core is a core or a core composed of one or more sheets. A portion of the bottom surface of the core (which may also be considered a top surface) is not covered by the coating material and is bare (see Figures 1, 2, 3).
  • the outer surface of the formulation is additionally coated with a coating which may or may not contain the active ingredient.
  • the coating layer is prepared by a compression coating process.
  • compositions selected from conventional pharmaceutical preparations such as fillers, disintegrants, lubricants, glidants, and the like. It is selected according to the needs of the technology in the art.
  • the filler is selected from one or more of lactose, pre-treated starch and microcrystalline cellulose;
  • the disintegrant is selected from sodium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch And one or more of crospovidone;
  • the lubricant is selected from one or more of stearic acid, magnesium stearate and talc;
  • the glidant is micronized silica gel or the like.
  • the tablet can be pressed in a conventional tablet press, but two different punches are required, and the general steps are as follows:
  • step 3 loading the pressed core of step 1) into the center of the middle mold, and performing the second pressing, that is, obtaining;
  • the diameter of the No. 1 punch is smaller than the diameter of the No. II punch.
  • the core of the step 1) is first loaded into the center of the middle mold, and then the uniformly mixed coating layer component is filled around the core of the middle mold to be subjected to secondary pressing.
  • the components of the different layers are sequentially released: the outermost layer is first released, and then the outer outer layer is released until the innermost layer of the inner core is finally released. In this way, the release sequence and timing of release of different drugs can be controlled.
  • the amount of the active ingredient in each layer of the inner core and the type and amount of the controlled release material by controlling the type and amount of the active ingredient and the controlled release material of the compression coating layer and
  • the amount of active ingredient is such that multiple pharmaceutically active ingredients are released at different times and at different times to achieve pulsed administration, achieving different release behaviors, such as zero-order release, first-order release, especially from slow to fast exponential release.
  • 1 is a schematic structural view of a controlled release sheet in which a core is a single layer, wherein 1 is a core and 2 is a coating;
  • 2 is a schematic structural view of a controlled release sheet of a two-layer tablet, wherein 1 is a core-release layer; 2 is a core-release layer; 3 is a coating;
  • 3 is a schematic structural view of a controlled release tablet in which the core is another two-layer tablet, wherein 1 is a core-sustained release layer; 2 is a core-sustained release 2 layer; 3 is a coating;
  • 4 to 7 are comparisons of dissolution profiles of the cores of Examples 1 to 4 and the controlled release tablets containing the same cores prepared by the method of the present invention, respectively. It can be seen that although the core is unchanged, when prepared as a controlled release preparation with a coating layer of a partially exposed core, the release behavior is significantly different, and it is easy to adapt to various clinical medication requirements;
  • FIG. 4 the in vitro dissolution of the drug can be changed from the first release to the zero-order release
  • FIG. 5 the drug can be slowly released first, and then released quickly
  • FIG. 6 The drug release rate is gradually getting faster
  • Figure 7 The drug can be released at a slow and constant rate according to different speeds
  • Figure 8 is a comparison of the dissolution profiles of the controlled release tablets of Example 1, Example 5, Example 6, and Example 7. It can be seen that the more the soluble material-lactose content in the coating, the faster the coating dissolution rate. ;
  • Example 9 is a comparison of the dissolution profiles of the controlled release tablets of Example 1, Example 8, Example 9, and Example 10. It can be seen that the more the content of the sustained release material in the core, the slower the dissolution rate of the core;
  • Example 10 is a schematic view showing the structure of a controlled release sheet of a three-layer core in Example 12, wherein 1 is a core-containing drug-containing layer; 2 is a core intermediate retardation layer; and 3 is a core lower layer drug-containing layer; 4 is a drug-containing coating; 5 is the outermost drug-containing film coating;
  • Figure 11 is a dissolution profile of the controlled release tablet of Example 12, showing the release mode of the combination of sustained release administration and pulsed administration.
  • the method for detecting drug dissolution in the present invention according to the first method of the XD release of the Chinese Pharmacopoeia 2010 edition, the first method (for sustained release, controlled release, delayed release preparation), the tablet is put into 900 ml 0.1 mol/L hydrochloric acid solution, Basket method, 100 rpm, 37 ° C, absorb the appropriate amount of dissolution at the specified sampling point to calculate the cumulative release of the tablets, draw a dissolution curve.
  • Example 1 The controlled release formulation in which the inner core is a single layer (only one sustained release layer)
  • the formulation comprises a core and a coating wrapped around the core, the core being a single layer having only one sustained release layer. As shown in Figure 1, a portion of the top surface of the inner core is not coated by the coating and is exposed to the surface of the solid formulation.
  • Each tablet weighs 800 mg in terms of 1000 tablets.
  • the drug was tested for dissolution and the dissolution profile is shown in Figure 4. It can be seen from the figure that the core release is in a first-order release trend, and after the outer coating is added to prepare a controlled release tablet, the tablet release is at a constant speed.
  • the active ingredient in the core can only be released through the top surface, and since the release area is constant, the zero-order release effect can be achieved.
  • the drug model prepared in Example 1 is suitable for cardiovascular and cerebrovascular drugs, and can replace the osmotic pump technology to achieve the purpose of constant drug release.
  • Example 2 The inner core is a two-layer (sustained release layer and immediate release layer) controlled release preparation
  • the formulation comprises a core and a coating wrapped around the core, the core being a two-layer sheet. As shown in Figure 2, a portion of the top surface of the inner core is not coated by the coating and is exposed to the surface of the solid formulation.
  • Each tablet weighs 800 mg in terms of 1000 tablets.
  • the drug was detected to be dissolved, and the dissolution profile is shown in Fig. 5. It can be seen from the figure that the individual cores disintegrate quickly because of the immediate release layer, the dissolution rate is faster, and the dissolution of the drug by 90% takes only 6 hours. When prepared as a controlled release tablet with a coating, the dissolution exhibited a tendency to slow first and then quickly.
  • the core of the tablet is composed of a sustained-release and quick-release two-layer tablet.
  • the sustained-release portion of the core is firstly dissolved, and the active component in the sustained-release layer is slowly released. After the sustained-release layer is released, the immediate release layer is rapidly released. Disintegration, for the purpose of rapid administration.
  • the drug model prepared in Example 2 is suitable for treating drugs such as morning stiffness and myocardial infarction, and the release time of the immediate release layer can be controlled after 4-6 hours after the administration of the drug, and the patient can avoid the drug before going to bed. The possibility of onset in the early hours.
  • the formulation comprises a core and a coating wrapped around the core, the core being a single layer having only one sustained release layer. As shown in Figure 1, a portion of the top surface of the inner core is not coated by the coating and is exposed to the surface of the solid formulation.
  • Each tablet weighs 800 mg in terms of 1000 tablets.
  • the drug was detected to be dissolved, and the dissolution profile is shown in Fig. 6. It can be seen from Fig. 6 that the individual cores are completely dissolved after 4 hours, and the drug release rate is over 90%. After the outer coating is coated to prepare the controlled release tablets, the drug release is slow within 4 hours, after 4 hours. The drug release rate is accelerated and the dissolution is completed at 8 hours.
  • the core of Example 3 is a single layer, the coating contains the active ingredient, and the coating material is selected from soluble hydroxypropylmethylcellulose.
  • the outer coating of the tablet gradually eroded, and the active ingredient in the coating was gradually released, which supplemented the problem that the drug was only released from the top surface and the cumulative release amount was insufficient.
  • the core is completely exposed, and the drug spreads from all sides, and the release amount increases.
  • This drug model can also be used as a treatment for diseases that occur at the time of the attack. The effect is similar to that of Embodiment 2.
  • Example 4 controlled release formulation with inner core as double layer (2 sustained release layers)
  • the preparation comprises a core and a coating wrapped outside the core, the core is a two-layer sheet, and consists of a sustained release layer and a sustained release layer. As shown in Figure 3, a portion of the top surface of the inner core is not coated by the coating and is exposed to the surface of the solid formulation.
  • Each tablet weighs 800 mg in terms of 1000 tablets.
  • the core-sustained release layer, the core-sustained release layer 2 raw materials are weighed, and then fully mixed and spared; two types of punches are selected, and the diameter of the No. I punch is smaller than II;
  • the drug was detected to be dissolved, and the dissolution profile is shown in Fig. 7. It can be seen from Fig. 7 that the core dissolution curve is released in the first order, and has been released by more than 30% in 0.5h, and the cumulative dissolution in 10 hours is more than 90%.
  • the release of the controlled release tablets exhibits two stages, namely, 0. The release rate is slow at ⁇ 5h, and the release rate is faster at 5 ⁇ 12h, but both stages are released at a constant rate.
  • the tablet core of Example 4 is a two-layer sheet composed of two different release rates, the upper layer is released slowly and the lower layer is released faster.
  • Example 5 The formulations of Examples 5 to 10 were the same as those of Example 1, and were controlled release preparations in which the inner core was a single layer (only one sustained release layer).
  • Each tablet weighs 800 mg in terms of 1000 tablets.
  • the patent also discloses the influence of the amount of the soluble component in the outer coating of the controlled release sheet and the content of the sustained release material in the core on the dissolution of the drug, and the preparation method is the same as that in the first embodiment.
  • Comparative Example 1, Example 8, Example 9, and Example 10 tablets were eluted. As can be seen from Fig. 9, the more the content of the sustained-release material in the core, the slower the dissolution rate of the core.
  • the inner core of the controlled release preparation of the present embodiment has three layers (each layer contains an active ingredient), and the incomplete coating layer also contains an active material, and the outermost film coat also contains an active material. As shown in Figure 10, a portion of the inner core containing drug layer is not coated. Coated and exposed to the surface of the solid preparation.
  • Each tablet weighs 800 mg in terms of 1000 tablets.
  • the drug dissolution was detected, and the dissolution curve is shown in Fig. 11. It can be seen that the drug release is pulsed, and the outermost film coat releases the drug first. After 15 minutes, the upper core begins to dissolve and release the drug; the intermediate core begins to release the drug after 1.5 hours. The lower core began to release after 3.5 hours. In addition, the drug in the compression coating continues to release the drug throughout the dissolution process after the outermost film coat is dissolved.

Abstract

一种控释固体制剂，由内芯和包衣层组成，所述内芯的部分表面不被包衣所包覆，而裸露于固体制剂的表面。由于药物仅在裸露的部位释放，通过控制此裸露的表面积，可以达到控制释放的目的。

Description

部分包衣的控释固体制剂
本申请针对以下中国专利申请提出优先权请求：
申请号：201410139563.9
申请日：2014-04-08
发明名称：一种新型控释片
技术领域
本发明属于制药技术领域，涉及一种部分包衣的控释固体制剂。
背景技术
在固体缓控释制剂中，经常采取活性药物通过缓控释材料包衣的方式。但这种方式有时不能达到预想的药物释放效果。例如，如果希望多个药物的活性成份能以不同的速度在预想的时间点释放，现有技术很难实现。较理想的药物释放方式是应该是：通过脉冲式给药获得不同释放行为，尤其是由慢到快的指数释放。目前的制剂达不到此效果。
因此，需要改变制剂的结构，达到控制释放行为的目的。
发明内容
本发明的目的是提供一种新结构的控释固体制剂，使药物的活性成份能以不同的释放速度在预想的时间点脉冲式释放，达到较理想的控制释放效果。
本发明设计了一种新结构的固体药物制剂，技术方案如下：
一种控释固体制剂，由内芯和包衣层组成，所述内芯含有活性药物和辅料，所述包衣层含有包衣材料并且或含有或不含有活性成分，其特征在于，所述内芯的部分表面不被包衣所包覆，而裸露于固体制剂的表面。
即，本发明制剂的包衣不完整包覆内芯，内芯的一部分裸露于固体制剂的表面。
在本发明的方案中，由于药物内芯部分裸露，便于通过该部分控制内芯药物的释放。
所述裸露部分，其部位、面积及形状不限，在实际应用中，根据具体制剂活性成分的释放要求和便于药剂生产，可以设计每种制剂的不同形状。
所述内芯是一层或多层，可以是一层或一层以上的缓释层，或者同时包含速释层与缓释层。
当内芯是两层或以上时，不同层的成分依次释放：先释放最外层，然后释放次外层，直 到最后释放内芯最内层的成分。通过此种方式，可以控制不同药物的释放顺序和释放时机。
所述缓释层的材料选自海藻酸钠、甲基纤维素、羟乙基纤维素、羟丙甲基纤维素、羟丙基纤维素、聚维酮或聚乙烯氧化物。
所述的包衣层的材料为水可溶性或水不溶性的；所述的水可溶性的包衣材料选自羟丙甲基纤维素、羟丙基纤维素中的一种或几种；所述的水不溶性的包衣材料选自乙基纤维素、醋酸纤维素聚合物、丙烯酸树脂中的一种或几种。
所述的包衣材料中还可以含有水溶性致孔剂，选自聚维酮、乳糖、氯化钠中的一种或几种。
当上述固体制剂是片剂时，其内芯是一层或由一层以上的片状物组成的片芯。片芯的一个底面(也可看作是顶面)的一部分未被包衣材料覆盖而裸露(见附图1、2、3)。
本发明的另一方案是，制剂的外表面另有一层包衣，所述包衣含有或不含有活性成分。
在本发明的又一种方案，所述包衣层由压制包衣法制备而成。
所述的内芯和包衣的成分中还包括药用辅料，选自常规药物制剂，例如填充剂、崩解剂、润滑剂、助流剂等。根据本领域技术的需要而选用。
比如，填充剂选自乳糖、预交化淀粉和微晶纤维素的一种或几种；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；润滑剂选自硬脂酸、硬脂酸镁和滑石粉的一种或几种；助流剂为微粉硅胶等。
本发明的固体制剂是片剂时，可在普通压片机中进行药片的压制，但需要使用两种不同规格的冲头，一般步骤如下：
1)将制备片芯的各组分混合，使用Ⅰ号冲头进行第一次压制，得到片芯；
2)更换Ⅱ号冲头，将制备包衣层的各组分混合后，装填入中模；
3)将步骤1)压制好的片芯装填到中模中央，进行第二次压制，即得；
所述Ⅰ号冲头的直径小于Ⅱ号冲头的直径。
上述方法中，所述步骤2)和3)也可以改为如下：
更换Ⅱ号冲头后，先将步骤1)压制好的片芯装填到中模中央，然后在中模内片芯周围装填入混合均匀的包衣层组分，进行二次压制。
本发明具有如下技术效果：
由于药物释放面仅在裸露的部位，通过控制此裸露的表面积，可以达到控制释放的目的。而且，由于药物不从未裸露部位释放，可以达到恒速释放的效果。
当内芯是两层或以上时，不同层的成分依次释放：先释放最外层，然后释放次外层，直到最后释放内芯最内层的成分。通过此种方式，可以控制不同药物的释放顺序和释放时机。
在本发明的制剂中，通过控制内芯中每一层的活性成份的量及缓控释材料的种类及用量，以及通过控制压制包衣层的活性成分及缓控释材料的种类及用量和活性成份的用量，使多个药物活性成份以不同的速度在不同时间释放，实现脉冲式给药，获得不同释放行为，如零级释放，一级释放，尤其是由慢到快的指数释放。
以上发明效果从各实施例得到的释放曲线中可以看出。
附图说明
图1为片芯是单层片的控释片的结构示意图，其中1为片芯，2为包衣；
图2为片芯是一种双层片的控释片的结构示意图，其中1为片芯-缓释层；2为片芯-速释层；3为包衣；
图3为片芯是另一种双层片的控释片的结构示意图，其中1为片芯-缓释1层；2为片芯-缓释2层；3为包衣；
图4～图7分别为实施例1～4中片芯和用本发明方法制备的含同样片芯的控释片的溶出曲线比较。可以看出，虽然片芯不变，当制备成带有部分裸露片芯的包衣层的控释制剂后，释放行为就有了明显的不同，便于适应各种临床用药要求；
从以上曲线可以看出，利用本发明的制备方法，图4：可改变药物体外溶出由一级释放变为零级释放；图5：可实现药物先缓慢释放，后快速释放；图6：可实现药物释放速度逐渐变快；图7：可实现药物按照不同的速度缓慢恒速释放；
图8为实施例1、实施例5、实施例6、实施例7中控释片的溶出曲线对照，可看出，包衣中可溶性材料—乳糖的含量越多，包衣溶出的速度越快；
图9为实施例1、实施例8、实施例9、实施例10中控释片的溶出曲线对照，可以看出片芯中缓释材料的含量越多，片芯溶出速度越慢；
图10为片芯是实施例12中三层片芯的控释片的结构示意图，其中1为片芯上层含药层；2为片芯中间阻滞层；3为片芯下层含药层；4为含药包衣；5为最外层含药薄膜包衣；
图11为实施例12中控释片的溶出曲线，可知缓释给药与脉冲式给药相结合的释药方式。
具体实施方式
本发明中的药物溶出检测方法：按照中国药典2010版二部附录XD释放度测定第一法(用于缓释、控释、迟释制剂)，将药片投入900ml 0.1mol/L盐酸溶液中，篮法，100转/分钟，37℃，在规定取样点吸取适量溶出液计算药片累计释放度，绘制溶出曲线。
实施例1内芯为单层(只有一个缓释层)的控释制剂
制剂包括片芯和包在片芯外的包衣，片芯为只有一个缓释层的单层片。如图1所示，内芯顶面的一部分不被包衣所包覆，裸露于固体制剂的表面。
成分和含量如下：按照1000片计，每片重800mg。
Figure PCTCN2015076028-appb-000001
制备方法：
1、将片芯原辅料按照处方进行称量，充分混合后备用；选择两种型号的冲头，Ⅰ号冲头直径小于Ⅱ号；
2、使用旋转式压片机，安装冲头Ⅰ，调整压片机填充深度和压片力，压制片芯，片重为每片300mg，片芯硬度90N；
3、按照处方称量包衣用辅料，充分混合备用；
4、使用旋转式压片机，安装冲头Ⅱ，调整压片机工艺参数，将压制好的片芯先放置在冲模中央，填加混合好的包衣材料，压制药片，使片芯的底面和侧面全部被包衣材料覆盖，药片总重800mg，硬度100N。
检测药物溶出，溶出曲线见图4。从图中可以看出：片芯释放呈一级释放趋势，添加了外层包衣制备成控释片后，药片释放呈恒速。
实施例1中，片芯仅顶面裸露在外，溶出过程中，片芯中的有效成分只能通过顶面释放，由于释放面积恒定，故可达到零级释放的效果。实施例1中制备的药物模型适合于心脑血管类药物，可以替代渗透泵技术达到药物恒速释放的目的。
实施例2内芯为双层(缓释层和速释层)的控释制剂
制剂包括片芯和包在片芯外的包衣，片芯为双层片。如图2所示，内芯顶面的一部分不被包衣所包覆，裸露于固体制剂的表面。
成分和含量如下：按照1000片计，每片重800mg。
Figure PCTCN2015076028-appb-000002
制备方法：
1、按照处方将片芯-缓释层、片芯-速释层原辅料进行称量，分别充分混合后备用；选择两种型号的冲头，Ⅰ号冲头直径小于Ⅱ号；
2、使用旋转式压片机，安装冲头Ⅰ，调整压片机填充深度和压片力，压制片芯，其中片芯-缓释层重为200mg，片芯-速释层重100mg，片芯硬度80N；
3、按照处方称量包衣用辅料，充分混合备用；
4、使用旋转式压片机，安装冲头Ⅱ，调整压片机工艺参数，将压制好的片芯带有颜色的速释层朝上先放置在冲模中央，填加混合好的包衣材料，压制药片，使片芯的底面和侧面全部被包衣材料覆盖，药片总重800mg，硬度100N。
检测药物溶出，溶出曲线见图5。从图中可以看出：单独的片芯因为速释层很快就崩解了，溶出速度较快，药物溶出90％仅需6小时。当制备成带有包衣的控释片后，溶出呈现了先慢，后快的释放趋势。
实施例2中片芯由缓释-速释双层片组成溶出过程中片芯中缓释部分先溶蚀，缓释层中的活性成份缓慢释放，待缓释层释放完毕后，速释层快速崩解，达到快速给药的目的。
实施例2中制备的药物模型适合于治疗晨僵、心梗等在凌晨易发病的药物，速释层释放的时间可以控制在药物服用后的4-6小时后，患者睡前服药后可避免凌晨发病的可能性。另外， 也适用于绝大部分在胃中吸收好，在胃的下部吸收较差的药物。低pH条件下，药物缓慢释放，释放的部分基本都能被吸收利用，当环境pH升高时，药物的溶解度降低，机体对药物的吸收变差，此时，增加药物的释放量可以弥补生物利用度低的问题。
实施例3内芯为单层(只有一个缓释层)的控释制剂
制剂包括片芯和包在片芯外的包衣，片芯为只有一个缓释层的单层片。如图1所示，内芯顶面的一部分不被包衣所包覆，裸露于固体制剂的表面。
成分和含量如下：按照1000片计，每片重800mg。
Figure PCTCN2015076028-appb-000003
制备方法：
1、将片芯原辅料按照处方进行称量，充分混合后备用；选择两种型号的冲头，Ⅰ号冲头直径小于Ⅱ号；
2、使用旋转式压片机，安装冲头Ⅰ，调整压片机填充深度和压片力，压制片芯，片重为每片300mg，片芯硬度90N；
3、按照处方称量包衣用辅料，充分混合备用；
4、使用旋转式压片机，安装冲头Ⅱ，调整压片机工艺参数，将压制好的片芯先放置在冲模中央，填加混合好的包衣材料，压制药片，使片芯的底面和侧面全部被包衣材料覆盖，药片总重800mg，硬度100N。
检测药物溶出，溶出曲线见图6。从图6可以看出：单独的片芯在4小时后即溶蚀完全，药物释放度达到90％以上，包被了外层包衣制备控释片后，4小时内药物释放缓慢，4小时以后药物释放速度加快，8小时溶出结束。
实施例3的片芯为单层片，包衣中含有活性成分，包衣材料选用可溶的羟丙甲基纤维素， 溶出实验中药片外层包衣逐渐溶蚀，包衣中的活性成分逐步释放，补充了药物仅从顶面释放，累计释放量不够的问题。待外壳溶蚀掉以后，片芯完全裸露在外，药物从四面开始扩散，释药量增加。这种药物模型也可以用于辰时发作的疾病的治疗药物。作用效果类似于实施例2。
实施例4内芯为双层(2个缓释层)的控释制剂
制剂包括片芯和包在片芯外的包衣，片芯为双层片，由缓释1层和缓释2层组成。如图3所示，内芯顶面的一部分不被包衣所包覆，裸露于固体制剂的表面。
成分和含量如下：按照1000片计，每片重800mg。
Figure PCTCN2015076028-appb-000004
制备方法：
1、按照处方将片芯-缓释1层、片芯-缓释2层原辅料进行称量，分别充分混合后备用；选择两种型号的冲头，Ⅰ号冲头直径小于Ⅱ号；
2、使用旋转式压片机，安装冲头Ⅰ，调整压片机填充深度和压片力，压制片芯，其中片芯-缓释1层重，片芯-缓释2层均重150mg，片芯总重300mg,硬度90N；
3、按照处方称量包衣用辅料，充分混合备用；
4、使用旋转式压片机，安装冲头Ⅱ，调整压片机工艺参数，将压制好的片芯带有颜色的速释层朝上先放置在冲模中央，填加混合好的包衣材料，压制药片，使片芯的底面和侧面全部被包衣材料覆盖，药片总重800mg，硬度100N。
检测药物溶出，溶出曲线见图7。从图7可以看出：片芯溶出曲线呈1级释放，0.5h即已释放30％以上，10小时累计溶出量达90％以上，控释片的释放呈现了两个阶段的特点，即0～5h时释放速度慢，5～12h释放速度变快，但两个阶段都呈恒速释放。
实施例4的药片片芯是由两种不同释放速度组成的双层片，上层释放速度慢，下层释放速度较快。
实施例5～10
实施例5～10的制剂同实施例1，均为内芯为单层(只有一个缓释层)的控释制剂。
成分和含量如下：按照1000片计，每片重800mg。
Figure PCTCN2015076028-appb-000005
另外本专利还公开了控释片外层包衣中可溶性成分的量和片芯中缓释材料含量对药物溶出的影响，制备方法同实施例1
比较实施例1、实施例5、实施例6、实施例7药片的溶出，从图8可以看出，包衣中可溶性材料—乳糖的含量越多，包衣溶出的速度越快。
比较实施例1、实施例8、实施例9、实施例10药片溶出，从图9可以看出，片芯中缓释材料的含量越多，片芯溶出速度越慢。
实施例11
本实施例中的控释制剂内芯为三层(每层都含有活性成分)，不完全包衣层中也含有活性物质，最外层薄膜衣中也含有活性物质。如图10所示，内芯上层含药层的一部分不被包衣所 包覆，裸露于固体制剂的表面。
成分和含量如下：按照1000片计，每片重800mg。
Figure PCTCN2015076028-appb-000006
制备方法：
1、按照处方将片芯的上层，中间层，下层原辅料进行称量，分别充分混合后备用；选择两种型号的冲头，Ⅰ号冲头直径小于Ⅱ号；
2、使用旋转式压片机，安装冲头Ⅰ，调整压片机填充深度和压片力，压制片芯，其中片 芯-上层重100mg，中间层重100mg，下层重100mg，片芯总重300mg，硬度100N；
3、按照处方称量包衣用辅料，充分混合备用；
4、使用旋转式压片机，安装冲头Ⅱ，调整压片机工艺参数，将压制好的片芯带有颜色的速释层朝上先放置在冲模中央，填加混合好的包衣材料，压制药片，使片芯的底面和侧面全部被包衣材料覆盖，药片总重800mg，硬度120N；
5、按照处方称量包衣粉，配制包衣液，使用高效包衣机包被最外层的薄膜衣，包衣增重2％。
检测药物溶出，溶出曲线见图11，可以看出：药物释放呈脉冲式，最外层薄膜衣先释放药物，15分钟后，上层片芯开始溶出释放药物；中间片芯1.5小时后开始释放药物；下层片芯3.5小时后开始释放。另外，压制包衣中的药物在最外层薄膜衣溶解后，在整个溶出过程中持续释放药物。

Claims (10)

  1. 一种控释固体制剂，由内芯和包衣层组成，所述内芯含有活性药物和辅料，所述包衣层含有缓控释材料并且或含有或不含有活性成分，其特征在于，所述内芯的表面不被包衣层完整包覆，部分裸露于固体制剂的表面。
  2. 权利要求1所述的固体制剂，所述内芯是一层或多层，且所述层是缓释层，或者同时包含速释层与缓释层；当内芯是两层或以上时，不同层的成分依次释放：先释放最外层，然后释放次外层，直到最后释放内芯最内层的成分。
  3. 权利要求1所述的固体制剂，所述包衣层由压制包衣法制备而成。
  4. 权利要求4所述的固体制剂，其特征在于，所述包衣层的材料为水可溶性或水不溶性的；所述水可溶性的包衣材料选自羟丙甲基纤维素、羟丙基纤维素中的一种或两种；所述水不溶性的包衣材料选自乙基纤维素、醋酸纤维素聚合物、丙烯酸树脂中的一种或几种。
  5. 权利要求1所述的固体制剂，其特征在于，所述的包衣层的材料中还可以含有水溶性致孔剂，选自聚维酮、乳糖、氯化钠中的一种或几种。
  6. 权利要求1-5中任一所述的固体制剂，在所述包衣层的外表面另有一层包衣，所述包衣含有或不含有活性成分。
  7. 权利要求1所述的固体制剂，是片剂。
  8. 权利要求7所述的固体制剂，其内芯是一层或由一层以上的片状物组成的片芯。
  9. 权利要求7或8所述的固体制剂的制备方法，在压片机中进行药片的压制，步骤如下：
    1)将制备片芯的各组分混合，使用Ⅰ号冲头进行第一次压制，得到片芯；
    2)更换Ⅱ号冲头，将制备包衣层的各组分混合后，装填入中模；
    3)将步骤1)压制好的片芯装填到中模中央，进行第二次压制，即得；
    所述Ⅰ号冲头的直径小于Ⅱ号冲头的直径。
  10. 权利要求9所述的制备方法，其中所述步骤2)和3)改为如下：
    更换Ⅱ号冲头后，先将步骤1)压制好的片芯装填到中模中央，然后在中模内片芯周围装填入混合均匀的包衣层组分，进行二次压制。
PCT/CN2015/076028 2014-04-08 2015-04-08 部分包衣的控释固体制剂 WO2015154656A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US15/302,977 US10413514B2 (en) 2014-04-08 2015-04-08 Controlled-release solid preparation with partial coating
EP15776295.6A EP3130334B8 (en) 2014-04-08 2015-04-08 Controlled-release solid preparation with partial coating
JP2017504225A JP7026876B2 (ja) 2014-04-08 2015-04-08 一部がコーティングされた放出制御固形製剤
DK15776295.6T DK3130334T3 (da) 2014-04-08 2015-04-08 Fast præparat til kontrolleret frigivelse med delvis coating
ES15776295T ES2939890T3 (es) 2014-04-08 2015-04-08 Preparación sólida de liberación controlada con recubrimiento parcial

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410139563.9 2014-04-08
CN201410139563.9A CN103948557A (zh) 2014-04-08 2014-04-08 一种新型控释片

Publications (1)

Publication Number Publication Date
WO2015154656A1 true WO2015154656A1 (zh) 2015-10-15

Family

ID=51326007

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/076028 WO2015154656A1 (zh) 2014-04-08 2015-04-08 部分包衣的控释固体制剂

Country Status (7)

Country Link
US (1) US10413514B2 (zh)
EP (1) EP3130334B8 (zh)
JP (1) JP7026876B2 (zh)
CN (1) CN103948557A (zh)
DK (1) DK3130334T3 (zh)
ES (1) ES2939890T3 (zh)
WO (1) WO2015154656A1 (zh)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104490838B (zh) * 2014-11-20 2017-03-01 河北医科大学 一种骨架型缓控释片剂及其制备方法和应用
CN105078918B (zh) * 2015-01-09 2018-04-17 田曼霖 一种醋酸地塞米松缓释制剂及其制备方法
CA2987114A1 (en) 2015-06-03 2016-12-08 Triastek, Inc. Method of 3d printing oral dosage forms having a drug in a compartment sealed by an erodibleplug
US11571391B2 (en) 2018-01-09 2023-02-07 Triastek, Inc. Oral drug dosage forms compromising a fixed-dose of an ADHD non-stimulant and an ADHD stimulant
CN117427043A (zh) * 2022-07-21 2024-01-23 越洋医药开发(广州)有限公司 一种双相控释制剂及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996007401A1 (de) * 1994-09-06 1996-03-14 Lts Lohmann Therapie-Systeme Gmbh Manteltablette mit spitzem kern
WO2005013935A2 (en) * 2003-08-07 2005-02-17 Sb Pharmco Puerto Rico Inc. Composition for releasing a weak base for an extended period of time
WO2008006216A1 (en) * 2006-07-14 2008-01-17 Mistral Pharma, Inc. Anti-inflammatory and cytoprotectant chronotherapy
WO2009002846A1 (en) * 2007-06-22 2008-12-31 Mcneil-Ppc, Inc. Laser marked dosage forms
CN102614141A (zh) * 2011-12-02 2012-08-01 内蒙古元和药业股份有限公司 一种盐酸维拉帕米迟释片剂及其制备方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922342A (en) * 1990-10-01 1999-07-13 Pharmacia & Upjohn Company Lateral edge coated controlled release pharmaceutical compositions
DE69229881T2 (de) * 1991-10-04 1999-12-09 Yoshitomi Pharmaceutical Tablette mit verzögerter freisetzung
US5582838A (en) * 1994-12-22 1996-12-10 Merck & Co., Inc. Controlled release drug suspension delivery device
IT1282576B1 (it) * 1996-02-06 1998-03-31 Jagotec Ag Compressa farmaceutica atta a cedere la sostanza attiva in tempi successivi e predeterminabili
US20050013863A1 (en) * 2003-07-18 2005-01-20 Depomed, Inc., A Corporation Of The State Of California Dual drug dosage forms with improved separation of drugs
DE60307819T2 (de) * 2003-07-30 2007-10-04 Pharmathen S.A., Pallini Venlafaxine Hydrochloridformulierungen mit verzögerter Freisetzung
CN101132777A (zh) * 2004-12-20 2008-02-27 科利吉姆制药公司 用于睡眠障碍的药物组合物
US8765178B2 (en) * 2006-07-19 2014-07-01 Watson Laboratories, Inc. Controlled release formulations and associated methods
CN101843598B (zh) * 2010-06-07 2015-10-07 常州制药厂有限公司 非洛地平缓释片的制备方法
AU2015274456B2 (en) 2014-06-11 2020-03-26 Massachusetts Institute Of Technology Self-assembled residence devices and related methods

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996007401A1 (de) * 1994-09-06 1996-03-14 Lts Lohmann Therapie-Systeme Gmbh Manteltablette mit spitzem kern
WO2005013935A2 (en) * 2003-08-07 2005-02-17 Sb Pharmco Puerto Rico Inc. Composition for releasing a weak base for an extended period of time
WO2008006216A1 (en) * 2006-07-14 2008-01-17 Mistral Pharma, Inc. Anti-inflammatory and cytoprotectant chronotherapy
WO2009002846A1 (en) * 2007-06-22 2008-12-31 Mcneil-Ppc, Inc. Laser marked dosage forms
CN102614141A (zh) * 2011-12-02 2012-08-01 内蒙古元和药业股份有限公司 一种盐酸维拉帕米迟释片剂及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3130334A4 *

Also Published As

Publication number Publication date
JP7026876B2 (ja) 2022-03-01
EP3130334A4 (en) 2017-12-06
JP2017510654A (ja) 2017-04-13
EP3130334A1 (en) 2017-02-15
EP3130334B8 (en) 2023-07-19
US10413514B2 (en) 2019-09-17
DK3130334T3 (da) 2023-03-13
US20170027872A1 (en) 2017-02-02
EP3130334B1 (en) 2023-02-15
ES2939890T3 (es) 2023-04-27
CN103948557A (zh) 2014-07-30

Similar Documents

Publication Publication Date Title
KR101378973B1 (ko) 구형에 가까운 형태의 다중 투여 단위 정제를 포함하는 경질 캡슐 복합 제형 및 이의 제조방법
KR100762847B1 (ko) 멀티플 유닛 타입 서방성 경구 제제 및 그 제조방법
WO2015154656A1 (zh) 部分包衣的控释固体制剂
US20230011269A1 (en) Pharmaceutical composition comprising a potent inhibitor of urat1
WO2011111818A1 (ja) モサプリドまたはその塩を含む徐放型医薬組成物
JP4970452B2 (ja) メトホルミン徐放性錠剤およびその製造方法
US20100092554A1 (en) Combination with an extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
JP2015511635A (ja) オルメサルタンメドキソミルとロスバスタチンまたはその塩とを含む医薬組成物
CN112472679A (zh) 双释放片及其制备方法
IL272352B2 (en) A pharmaceutical preparation containing 3-fluoro-4-[7-methoxy-3-methyl-8-(1-methyl-1 H-pyrazol-4-yl)-2-oxo-2,3-dihydro-imidazo[5,4 -C]quinolin-1-yl]-benzonitrile
CN103655505B (zh) 一种止痛类双层控释片及其制备方法
KR20070069105A (ko) 서방성 제제
CN101990427A (zh) 米格列奈及二甲双胍的复合制剂及其制造方法
KR20150075961A (ko) 속방층과 2개의 서방층으로 이루어진 위장관 질환 치료용 모사프리드 구연산염 삼층정 서방제제
KR20150075960A (ko) 펠렛이 매트릭스에 분산된 모사프리드 구연산염 함유 서방형 매트릭스 제제 및 이의 제조 방법
CN111991399A (zh) 一种含有替格瑞洛和阿司匹林的复合包装制剂
TW202143972A (zh) 一種替格瑞洛的多元製劑
CN116159033B (zh) 一种氨氯地平贝那普利固体制剂及其制备工艺
KR20090107960A (ko) 심혈관계 질환 치료용 약제학적 제제
KR102246066B1 (ko) 레보드로프로피진 함유 서방정의 제조방법
KR20120092993A (ko) 티아넵틴 또는 이의 약제학적으로 허용되는 염을 포함하는 경구투여용 서방성 정제
CN114533694A (zh) 一种含有替格瑞洛和阿司匹林的复方胶囊制剂及其制备方法
CN115006361A (zh) 一种托法替布缓释包芯片及其制备方法
CN201197815Y (zh) 氯雷伪麻双释胶囊
EP2554164A1 (en) Pharmaceutical formulation based on ibuprofen and codeine having having improved stability

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15776295

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15302977

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017504225

Country of ref document: JP

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2015776295

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015776295

Country of ref document: EP