WO2017156953A1 - 一种盐酸二甲双胍渗透泵片及其制备方法 - Google Patents

一种盐酸二甲双胍渗透泵片及其制备方法 Download PDF

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WO2017156953A1
WO2017156953A1 PCT/CN2016/091933 CN2016091933W WO2017156953A1 WO 2017156953 A1 WO2017156953 A1 WO 2017156953A1 CN 2016091933 W CN2016091933 W CN 2016091933W WO 2017156953 A1 WO2017156953 A1 WO 2017156953A1
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metformin hydrochloride
osmotic pump
core
weight
preparation
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PCT/CN2016/091933
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English (en)
French (fr)
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田武
李伟
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赛乐医药科技(上海)有限公司
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Priority to US16/084,416 priority Critical patent/US10668021B2/en
Publication of WO2017156953A1 publication Critical patent/WO2017156953A1/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
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and relates to a metformin hydrochloride osmotic pump sheet and a preparation method thereof, in particular to a metformin hydrochloride osmotic pump sheet prepared by using a profiled punch and a preparation method thereof.
  • metformin hydrochloride sustained-release tablets as an example, the two commonly used specifications are 500 mg and 1000 mg.
  • the metformin hydrochloride sustained-release tablets marketed on the Chinese pharmaceutical market use a skeleton-type controlled release mechanism to control drug release, 500 mg specification.
  • the skeletal sustained-release tablet weighs more than 1 gram (about 1.1 gram).
  • the tablet type uses a capsule tablet to reduce the cross-sectional area through the esophagus when swallowed. If the 1000 mg size skeleton sustained release tablet is produced by the sustained release of the skeleton, the weight will reach 2 g. Even with the capsule design, the volume is too large, which will make it difficult for patients to swallow. Therefore, the maximum size of metformin hydrochloride sustained-release tablets marketed in China is only 500 mg, and there is no 1000 mg of metformin hydrochloride sustained-release tablets.
  • metformin hydrochloride osmotic pump tablets (trade name: FORTMET) manufactured by Andrx Labs. Because the osmotic pump preparation uses coated film as a controlled release means, it can be more The less excipients achieve a slow release effect, so the total weight of the preparation is only about 1.2 grams, which is much lower than the weight of the skeleton type sustained release tablets (more than 2 grams).
  • FORTMET osmotic pump piece adopts a circular stamping core, and the punch used for preparing the osmotic pump sheet is a circular punch.
  • the core of the round stamping is isotropic, and during the coating process, the core is processed.
  • the tumbling in the coating pan is random, and the probability of receiving the coating liquid in each direction is the same. Therefore, the coating film on the entire surface of the tablet is relatively uniform, so that the coating film has good integrity and is not easily broken. release.
  • the FORTMET osmotic pump plate uses a circular punched core with a diameter of 13 to 14 mm.
  • the tablet weight is significantly lower than that of the skeleton type sustained release tablet, the cross-sectional area is still large and it is still inconvenient to swallow.
  • the present invention provides a metformin hydrochloride osmotic pump sheet and a preparation method thereof, and the method of the present invention adopts a special-shaped stamping hydrochloric acid.
  • the present invention provides a metformin hydrochloride osmotic pump sheet and a preparation method thereof. Metformin core was prepared, and then a controlled release coating film was prepared by pressing a modified Metformin hydrochloride core to form a metformin hydrochloride osmotic pump sheet.
  • the metformin hydrochloride osmotic pump sheet prepared by the invention has a small tablet weight, and the 1000mg specification metformin hydrochloride osmotic pump sheet has a tablet weight of only about 1.2g; and the use of the special-shaped stamping core makes the metformin osmotic pump sheet
  • the cross-sectional area is reduced by more than 40% compared to the cross-sectional area of the round piece of the same weight, which greatly improves the swallowability of the tablet.
  • the present invention provides a preparation method of a metformin hydrochloride osmotic pump sheet, which is prepared by using a special-shaped stamping process for preparing a metformin hydrochloride core, and is prepared by pressing a controlled release film of a metformin hydrochloride core.
  • Metformin hydrochloride osmotic pump tablets are prepared by using a special-shaped stamping process for preparing a metformin hydrochloride core, and is prepared by pressing a controlled release film of a metformin hydrochloride core.
  • the method includes the following steps:
  • the shaped punch is a capsule punch or an oval punch.
  • the ratio of the length of the major axis to the minor axis of the metformin hydrochloride core is controlled to be 1.2 to 4, such as 1.2, 1.3, 1.5, 1.8, 2.0, 2.2, 2.5, 2.8, 3.0, 3.2, 3.5. 3.8, 3.9 or 4, etc., but not limited to the numerical values listed, other values in the range listed may be used, further preferably 1.5 to 3, and the ratio of the length of the long diameter to the short diameter is 1.8 to 2.7. The most excellent.
  • a problem in the presence of a non-circular (e.g., capsule or elliptical) core obtained by a profiled press to prepare a metformin hydrochloride osmotic pump sheet is due to non-circular (e.g., capsule or oval) sheets.
  • the core is not as isotropic as a circular core, so the movement of a non-circular (eg, capsule or elliptical) core in the coating pan tends to roll in the coating pan with the long diameter as the axis, so Non-circular (eg, capsule or elliptical) cores are less likely to receive coating liquid at both ends than in the middle.
  • This type of motion results in a non-circular (eg, capsule or elliptical) core of the controlled release coating that may not be uniform enough, especially the core
  • the controlled release coating at both ends is likely to be thinner than the controlled release coating in the middle of the tablet, which may result in rupture of the osmotic pump during release, posing a risk of drug burst.
  • the invention has been repeatedly verified by experiments and concluded that when the ratio of the length of the long diameter to the short diameter of the non-circular (such as capsule or elliptical) core is greater than 4, the controlled release coating film at both ends of the core is significantly larger than the core
  • the controlled release film in the middle is thin, in order to make the controlled release film not damaged, it is necessary to greatly increase the thickness of the controlled release film (for example, 20% by weight of the coating weight gain), under which the release rate of the tablet will be Significantly affected, when the osmotic pump sheet is designed as a shaped piece, the ratio of the length of the long diameter to the short diameter of the metformin hydrochloride core should be controlled to 1.2 to 4, wherein the length of the long diameter and the short diameter The ratio of 1.8 to 2.7 is the most excellent.
  • the drug release channel is prepared on the controlled release coating film wrapped by the metformin hydrochloride osmotic pump sheet.
  • the drug release channel can be prepared on the controlled release coating film wrapped by the metformin hydrochloride osmotic pump sheet, or the drug release channel can be prepared.
  • the drug release channel is not prepared, the drug can be dissolved by the porogen. The hole is released.
  • the number of the drug delivery channels is ⁇ 1, such as 1, 2, 3, 4 or 5 and more, and is not limited to the numerical values listed above.
  • the weight of the controlled release coating film is ⁇ 2 wt%, for example, 2 wt%, 2.1 wt%, 2.3 wt%, 2.5 wt%, based on the weight of the core. 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 12 wt%, 15 wt%, 18 wt% or 20 wt%, etc., but not limited to the recited values, further preferably 2.5 to 10% by weight, particularly preferably 3 to 8% by weight.
  • the weight gain of the controlled release film also affects the integrity of the controlled release film. If the controlled release film is too thin, the ends of the non-circular (such as capsule or oval) core cannot be wrapped. The possibility of releasing the film is higher, so the weight gain of the controlled release film should be at least 2% by weight of the core weight.
  • the step (1) prepares the binder solution by mixing the binder with a solvent to prepare a binder solution.
  • the binder is any one or a combination of at least two of povidone, hypromellose or hydroxypropyl cellulose, typical but non-limiting examples of which are: povidone and A combination of hypromellose, a combination of hypromellose and hydroxypropylcellulose, a combination of povidone, hypromellose and hydroxypropylcellulose.
  • the solvent is ethanol and/or water having a purity of 95% by weight.
  • the binder is povidone
  • the mass ratio of povidone to ethanol having a purity of 95 wt% is (10-15): (90-85), for example. 10:90, 11:89, 12:88, 13:87, 14:86 or 15:85, etc., but not limited to the numerical values listed, other values in the range listed can be carried out, and further preferably 15:85.
  • the binder is hypromellose
  • the mass ratio of hypromellose to water is (10-15): (290-285), for example, 10:290, 11: 289, 12:288, 13:287, 14:286 or 15:285, etc., but not limited to the numerical values listed, other values in the range listed may be carried out, and further preferably 15:285.
  • the core excipient in the step (1) comprises sodium lauryl sulfate and a filler.
  • the filler is any one or a combination of at least two of polysorbate, sorbitol or mannitol, and typical but non-limiting examples of the combination are: a combination of polysorbate and sorbitol, Yamanashi A combination of an alcohol and mannitol, a combination of polysorbate and mannitol, a combination of polysorbate, sorbitol and mannitol.
  • the binder solution, metformin hydrochloride, sodium lauryl sulfate and the filler in the step (1) are mixed in the following parts by weight:
  • the sodium dodecyl sulfate may be 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts by weight. Or 70 parts, etc., but not limited to the numerical values listed, other values in the range listed can be used; the filler can be 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts by weight.
  • the weight ratio of the binder solution can be 95 parts, 100 parts 120 parts, 150 parts, 170 parts, 200 parts, 230 parts, 250 parts, 270 parts or 300 parts, etc., but are not limited to the numerical values listed, and other values in the range listed can be used.
  • the binder solution, metformin hydrochloride, sodium lauryl sulfate and polysorbate in step (1) are mixed in the following parts by weight:
  • the binder solution, metformin hydrochloride, sodium lauryl sulfate and mannitol in step (1) are mixed in the following parts by weight:
  • a lubricant is added during the sizing process in the step (1).
  • the lubricant is magnesium stearate.
  • the lubricant is added in an amount of 0.5 to 1% by mass of metformin hydrochloride, for example, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%, etc., but is not limited to the numerical values listed. Other values in the column range are OK.
  • the coating liquid used in the process of wrapping the controlled release coating film comprises a controlled release material and a porogen.
  • the coating liquid may contain other active ingredients in addition to the controlled release material and the porogen.
  • the controlled release material is cellulose acetate and/or ethyl cellulose.
  • the porogen is polyethylene glycol.
  • the coating liquid consists essentially of the following components in parts by weight:
  • the weight fraction of cellulose acetate and/or ethyl cellulose may be 20 parts, 22 parts, 24 parts, 26 parts, 28 parts or 30 parts, etc., but is not limited to the listed values, and other ranges are listed. Values can be used;
  • the weight fraction of the polyethylene glycol may be 10 parts, 12 parts, 14 parts, 16 parts, 18 parts or 20 parts, etc., but is not limited to the numerical values listed, and other values in the range listed may be used;
  • the solvent may be used in an amount of 750 parts, 752 parts, 754 parts, 756 parts, 758 parts or 760 parts, etc., but is not limited to the numerical values listed, and other values in the range listed may be used.
  • the solvent is any one or a combination of at least two of ethanol, acetone or water.
  • the present invention provides a metformin hydrochloride osmotic pump tablet prepared by the above preparation method, comprising a metformin hydrochloride tablet core and a controlled release coating film wrapped around a core of metformin hydrochloride, wherein the long diameter of the metformin hydrochloride osmotic pump sheet is
  • the ratio of the length of the short diameter is 1.2 to 4, such as 1.2, 1.3, 1.5, 1.8, 2.0, 2.2, 2.5, 2.8, 3.0, 3.2, 3.5, 3.8, 3.9 or 4, etc., but is not limited to the numerical values listed. Other values in the range listed may be carried out, and further preferably 1.5 to 3, and particularly preferably 1.8 to 2.7.
  • the metformin hydrochloride osmotic pump sheet has a non-circular shape.
  • the metformin hydrochloride osmotic pump sheet has a shape of a capsule.
  • the metformin hydrochloride osmotic pump sheet has an elliptical shape.
  • the present invention has the following beneficial effects:
  • the method of the invention adopts a special-shaped stamping process for preparing a metformin hydrochloride tablet core, and then preparing a controlled release coating film on the pressed metformin hydrochloride core to form a metformin hydrochloride osmotic pump sheet.
  • the metformin hydrochloride osmotic pump sheet prepared by the invention has a small tablet weight, and the 1000mg specification metformin hydrochloride osmotic pump sheet has a tablet weight of only about 1.2g; and the prepared metformin hydrochloride osmotic pump sheet reaches the prior art.
  • the cross-sectional area of the osmotic pump sheet of the same weight is greatly reduced compared with the conventional slow-release tablet, and can even be reduced by more than 50%, so that the obtained osmotic pump tablet is easier to swallow, and the pole is more easily swallowed. Greatly improved patient compliance.
  • Figure 1 is a schematic view showing the shape of the metformin hydrochloride osmotic pump sheet of the present invention
  • Example 2 is a release curve of a metformin hydrochloride osmotic pump sheet prepared in Example 1 of the present invention
  • Figure 3 is a graph showing the release profile of a metformin hydrochloride osmotic pump tablet prepared in Example 1 of the present invention.
  • a specific embodiment of the present invention provides a metformin hydrochloride osmotic pump sheet and a preparation method thereof, the preparation method comprising the following steps:
  • the granules obtained by granulating are mixed with magnesium stearate at a rotation speed of 25 r/min for 10 minutes, and then formed into a tablet core containing 1000 mg of metformin hydrochloride in a capsule shape of 19 x 7.9 mm;
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, and the ratio of the length of the long diameter to the short diameter is 2.4, and the cross-sectional area is larger than that of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 50%, and the sustained-release curve is shown in Fig. 1. It can be seen that the metformin hydrochloride osmotic pump sheet reaches the same as the prior art in the phosphate buffer solution of the paddle method 50r/min and pH 6.8. control Drug release effect.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, and the ratio of the length of the long diameter to the short diameter is 2.4, and the cross-sectional area is larger than that of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 50%, and the sustained-release curve is shown in Fig. 2. It can be seen that the metformin hydrochloride osmotic pump sheet reaches the same as the prior art in the phosphate buffer solution of the paddle method 50r/min and pH 6.8. Control the release of the drug.
  • Example 1 except for the raw materials used, the ratio shown in Table 3 was used, and an elliptical punch of 19 ⁇ 15.8 mm was used, and when the weight gain of the coating reached about 3%, the coating was stopped, and the other materials and preparation methods were The same is true in Example 1.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, and the ratio of the length of the long diameter to the short diameter is 1.2, and the cross-sectional area is larger than that of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 40 to 50%, which can achieve the same control drug release effect as the prior art.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, a ratio of the length of the long diameter to the short diameter of 4, and a cross-sectional area of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 40 to 50%, which can achieve the same control drug release effect as the prior art.
  • Example 1 except for the raw materials used, the ratio shown in Table 5 was used, and an elliptical punch of 19 ⁇ 7.9 mm was used, and when the weight gain of the coating reached about 2.5%, the coating was stopped, and other materials and preparation methods were used. The same is true in Example 1.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, and the ratio of the length of the long diameter to the short diameter is 2.4, and the cross-sectional area is larger than that of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 40 to 50%, which can achieve the same control drug release effect as the prior art.
  • Example 1 except for the raw materials used, the ratio shown in Table 6 was used, and an elliptical punch of 19 x 7.9 mm was used, and when the weight gain of the coating reached about 10%, the coating was stopped, and other materials and preparation methods were used. The same is true in Example 1.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, and the ratio of the length of the long diameter to the short diameter is 2.4, and the cross-sectional area is larger than that of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 40 to 50%, which can achieve the same control drug release effect as the prior art.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, and the ratio of the length of the long diameter to the short diameter is 1.8, and the cross-sectional area is larger than that of the conventional sustained-release tablet (using a circular shape). Flush Pressing) can be reduced by 40 to 50%, which can achieve the same controlled drug release effect as the prior art.
  • the 1000mg specification metformin hydrochloride osmotic pump tablet prepared in this embodiment has a tablet weight of only about 1.2g, and the ratio of the length of the long diameter to the short diameter is 2.7, and the cross-sectional area is larger than that of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 40 to 50%, which can achieve the same control drug release effect as the prior art.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, a ratio of the length of the long diameter to the short diameter of 3, and a cross-sectional area of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 40 to 50%, which can achieve the same control drug release effect as the prior art.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this embodiment has a tablet weight of only about 1.2g, a ratio of the length of the long diameter to the short diameter of 1.5, and a cross-sectional area of the conventional sustained-release tablet (using a circular shape).
  • the stamping system can be reduced by 40 to 50%, which can achieve the same control drug release effect as the prior art.
  • the 1000mg specification metformin hydrochloride osmotic pump sheet prepared in this example has a tablet weight of only about 1.2g, and the ratio of the length of the long diameter to the short diameter is 2.4, and the cross-sectional area is larger than that of the conventional sustained-release tablet (using circular punching) System) can be reduced by 50%.
  • the method of the present invention uses a special-shaped stamping process to form a metformin hydrochloride tablet core, and then a controlled release coating film is formed on the pressed metformin hydrochloride core to form a metformin hydrochloride osmotic pump sheet.
  • the metformin hydrochloride osmotic pump sheet prepared by the invention has a small tablet weight, and the 1000mg specification metformin hydrochloride osmotic pump sheet has a tablet weight of only about 1.2g; the obtained metformin hydrochloride osmotic pump sheet is the same as the prior art.
  • the cross-sectional area of the osmotic pump sheet of the same weight is greatly reduced compared with the conventional slow-release tablet, and can even be reduced by more than 50%, so that the obtained osmotic pump tablet is easier to swallow, which is extremely large. Improve patient compliance.

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Abstract

一种盐酸二甲双胍渗透泵片及其制备方法，制备方法为:采用异型冲压制盐酸二甲双胍片芯，在经过压制的盐酸二甲双胍片芯外包裹控释衣膜制成盐酸二甲双胍渗透泵片。

Description

一种盐酸二甲双胍渗透泵片及其制备方法 技术领域
本发明属于药物制剂领域，涉及一种盐酸二甲双胍渗透泵片及其制备方法，尤其涉及一种采用异型冲制备得到的盐酸二甲双胍渗透泵片及其制备方法。
背景技术
随着药学科学的发展，口服缓控释制剂相对于普通速释制剂的治疗优势已经被人们所认识，缓控释制剂释药时间更长、药物释放更加平稳，从而使得患者体内的血浆药物浓度波动降低，既减少了服药次数，又提高了治疗效果，同时还减少副作用的发生。因此在药物制剂的研发过程中，越来越多的药物被设计成缓控释制剂。
在实际应用中，为了达到控制药物释放的目的，往往需要使用较多的控制药物释放的辅料，然而大量辅料的使用必然导致最终制剂的重量和体积较大，从而给病人吞咽药物造成困难。根据美国FDA的统计数据，美国有1600万人有吞咽困难，在这其中，有8％的人发生过由于制剂太大难以吞咽而没有严格按医嘱服用药物的情况，更有4％的人由于无法咽下某种制剂而放弃了使用该种制剂进行治疗，因此控制药物制剂的重量和体积，使之易于病人吞咽是一个与药物治疗效果息息相关的课题。
以盐酸二甲双胍骨架型缓释片为例，其两个常用规格为500毫克和1000毫克，中国药品市场上市的盐酸二甲双胍缓释片均采用骨架型缓控释机理控制药物的释放，500毫克规格的骨架型缓释片重量在1克以上(约1.1克)，为了便于病人服用，片型采用胶囊型片剂，以减小其吞咽时通过食道方向的横截面积。如果以骨架缓释的方法生产1000毫克规格的骨架型缓释片，重量将达到2克以 上，即使采用胶囊型的设计，仍然体积太大，将导致病人很难吞咽，因此中国市场上市的盐酸二甲双胍缓释片最大规格只有500毫克，而没有1000毫克规格的盐酸二甲双胍缓释片。
在美国市场上市的盐酸二甲双胍缓控释制剂中，有Andrx Labs生产的规格为1000毫克的盐酸二甲双胍渗透泵片(商品名FORTMET)，由于渗透泵制剂以包衣膜作为控释手段，能以更少的辅料达到缓控释效果，因此该制剂的总重量仅为1.2克左右，大大低于骨架型缓释片的重量(超过2克)。FORTMET渗透泵片采用圆形冲压制片芯，制备渗透泵片所用的冲均为圆形冲，其原因是圆形冲压制的片芯是各项同性的，在包衣的过程中，片芯在包衣锅中翻滚是随机的，每个方向接受包衣液的概率相同，因此，整个片剂表面的包衣膜较为均匀，从而使包衣膜完整性较好，不容易破裂而产生突释。然而FORTMET渗透泵片采用的是直径为13～14毫米的圆形冲压制片芯，虽然片重比骨架型缓释片明显降低，但是横截面积仍然很大，仍然不便于吞咽。
发明内容
针对现有技术存在的盐酸二甲双胍缓控释制剂的横截面积大，不便于吞咽等问题，本发明提供了一种盐酸二甲双胍渗透泵片及其制备方法，本发明所述方法采用异型冲压制盐酸二甲双胍片芯，然后在经过压制的盐酸二甲双胍片芯外包裹控释衣膜制成盐酸二甲双胍渗透泵片。本发明制得的盐酸二甲双胍渗透泵片的片重较小，1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右；并且由于采用了异型冲压制片芯，使得二甲双胍渗透泵片的横截面积比相同重量的圆型片的横截面积降低40％以上，大大提高了片剂的易吞咽性。
为达此目的，本发明采用以下技术方案：
第一方面，本发明提供了一种盐酸二甲双胍渗透泵片的制备方法，所述制备方法为：采用异型冲压制盐酸二甲双胍片芯，在经过压制的盐酸二甲双胍片芯外包裹控释衣膜制成盐酸二甲双胍渗透泵片。
以下作为本发明优选的技术方案，但不作为本发明提供的技术方案的限制，通过以下技术方案，可以更好的达到和实现本发明的技术目的和有益效果。
作为本发明优选的技术方案，所述方法包括以下步骤：
(1)配制粘合剂溶液，将盐酸二甲双胍、片芯辅料与粘合剂溶液进行混合制粒，然后进行干燥和整粒；
(2)经整粒得到的颗粒采用异型冲压制成盐酸二甲双胍片芯；
(3)在制得的盐酸二甲双胍片芯外包裹控释衣膜，得到盐酸二甲双胍渗透泵片。
作为本发明优选的技术方案，所述异形冲为胶囊形冲或椭圆形冲。
优选地，采用异型冲时，控制盐酸二甲双胍片芯的长径与短径的长度之比为1.2～4，例如1.2、1.3、1.5、1.8、2.0、2.2、2.5、2.8、3.0、3.2、3.5、3.8、3.9或4等，但并不仅限于所列举的数值，所列范围内其他数值均可行，进一步优选为1.5～3，又以长径与短径的长度之比为1.8～2.7的效果最为优异。
本发明中，采用异形冲压制得到的非圆形(如胶囊形或椭圆形)片芯来制备盐酸二甲双胍渗透泵片的存在的一个问题是：由于非圆形(如胶囊形或椭圆形)片芯不像圆形片芯一样各向同性，因此非圆形(如胶囊形或椭圆形)片芯在包衣锅中的运动状态更加倾向于以长径为轴在包衣锅中滚动，因此非圆形(如胶囊形或椭圆形)片芯的两端接受包衣液的几率要小于中部。这样的运动方式导致非圆形(如胶囊形或椭圆形)片芯的控释衣膜可能不够均匀，尤其是片芯 两端的控释衣膜很可能比片剂的中部的控释衣膜薄，因此可能导致渗透泵片在释放过程中破裂，造成药物突释的风险。
上述问题，尤其是在非圆形(如胶囊形或椭圆形)片芯的长径与短径的长度之比越大时越明显，因为长径与短径的长度之比越大，片芯就越细长，于是片芯两端接受到包衣液的概率就越低，衣膜不均匀的可能性也就越高。本发明经过反复实验验证和总结得出，非圆形(如胶囊形或椭圆形)片芯的长径与短径的长度之比大于4时，片芯两端的控释衣膜显著比片芯中部的控释衣膜要薄，为了使控释衣膜不破损，则需要大幅度增加控释衣膜的厚度(例如20wt％的包衣增重)，在此条件下片剂的释放速率将受到显著的影响，因此在将渗透泵片设计成异型片的时候，应控制盐酸二甲双胍片芯的长径与短径的长度之比为1.2～4，其中，又以长径与短径的长度之比为1.8～2.7的效果最为优异。
优选地，所述盐酸二甲双胍渗透泵片外包裹的控释衣膜上制备有释药孔道。本发明中，所述盐酸二甲双胍渗透泵片外包裹的控释衣膜上可以制备释药孔道，也可不制备释药孔道，当不制备释药孔道时，药物可以通过致孔剂溶解后留下的孔道释放。
优选地，所述释药孔道的个数≥1，例如1、2、3、4或5以及更多，并不仅限于上述所列举的数值。
作为本发明优选的技术方案，盐酸二甲双胍片芯包裹控释衣膜后，以片芯重量计，控释衣膜增重≥2wt％，例如2wt％、2.1wt％、2.3wt％、2.5wt％、3wt％、4wt％、5wt％、6wt％、7wt％、8wt％、9wt％、10wt％、12wt％、15wt％、18wt％或20wt％等，但并不仅限于所列举的数值，进一步优选为2.5～10wt％，特别优选为3～8wt％。
本发明中，控释衣膜增重对控释衣膜的完整性也有影响，若控释衣膜太薄，则非圆形(如胶囊形或椭圆形)片芯的两端无法包裹住控释衣膜的可能性就更高，因此控释衣膜增重至少应为片芯重量的2wt％以上。
作为本发明优选的技术方案，步骤(1)配制粘合剂溶液为：将粘合剂与溶剂混合配制成粘合剂溶液。
优选地，所述粘合剂为聚维酮、羟丙甲纤维素或羟丙基纤维素中任意一种或至少两种的组合，所述组合典型但非限制性实例有：聚维酮和羟丙甲纤维素的组合，羟丙甲纤维素和羟丙基纤维素的组合，聚维酮、羟丙甲纤维素和羟丙基纤维素的组合等。
优选地，所述溶剂为纯度为95wt％的乙醇和/或水。
优选地，所述粘合剂为聚维酮，溶剂为纯度为95wt％的乙醇时，聚维酮与纯度为95wt％的乙醇的质量比为(10～15)∶(90～85)，例如10∶90、11∶89、12∶88、13∶87、14∶86或15∶85等，但并不仅限于所列举的数值，所列范围内其他数值均可行，进一步优选为15∶85。
优选地，所述粘合剂为羟丙甲纤维素，溶剂为水时，羟丙甲纤维素与水的质量比为(10～15)∶(290～285)，例如10∶290、11∶289、12∶288、13∶287、14∶286或15∶285等，但并不仅限于所列举的数值，所列范围内其他数值均可行，进一步优选为15∶285。
作为本发明优选的技术方案，步骤(1)中所述片芯辅料包括十二烷基硫酸钠和填充剂。
优选地，所述填充剂为聚山梨醇、山梨醇或甘露醇中任意一种或至少两种的组合，所述组合典型但非限制性的实例有：聚山梨醇和山梨醇的组合，山梨 醇和甘露醇的组合，聚山梨醇和甘露醇的组合，聚山梨醇、山梨醇和甘露醇的组合等。
优选地，步骤(1)中粘合剂溶液、盐酸二甲双胍、十二烷基硫酸钠和填充剂按如下重量份进行混合：
Figure PCTCN2016091933-appb-000001
其中，十二烷基硫酸钠的重量份可为5份、10份、15份、20份、25份、30份、35份、40份、45份、50份、55份、60份、65份或70份等，但并不仅限于所列举的数值，所列范围内其他数值均可行；填充剂的重量份可为100份、105份、110份、115份、120份、125份、130份、135份、140份、145份、150份或155份等，但并不仅限于所列举的数值，所列范围内其他数值均可行；粘合剂溶液的重量份可为95份、100份、120份、150份、170份、200份、230份、250份、270份或300份等，但并不仅限于所列举的数值，所列范围内其他数值均可行。
优选地，步骤(1)中粘合剂溶液、盐酸二甲双胍、十二烷基硫酸钠和聚山梨醇按如下重量份进行混合：
Figure PCTCN2016091933-appb-000002
优选地，步骤(1)中粘合剂溶液、盐酸二甲双胍、十二烷基硫酸钠和甘露醇按如下重量份进行混合：
Figure PCTCN2016091933-appb-000003
作为本发明优选的技术方案，步骤(1)所述整粒过程中加入润滑剂。
优选地，所述润滑剂为硬脂酸镁。
优选地，所述润滑剂的加入量为盐酸二甲双胍质量的0.5～1％，例如0.5％、0.6％、0.7％、0.8％、0.9％或1％等，但并不仅限于所列举的数值，所列范围内其他数值均可行。
作为本发明优选的技术方案，所述包裹控释衣膜过程中所用的包衣液包括控释材料和致孔剂。本发明中，所述包衣液除了包括控释材料和致孔剂外，还可添加其他有效成分。
优选的，所述控释材料为醋酸纤维素和/或乙基纤维素。
优选地，所述致孔剂为聚乙二醇。
优选地，所述包衣液主要由以下组分按重量份计组成：
控释材料                  20～30份
致孔剂                    10～20份
溶剂                      750～760份；
其中，醋酸纤维素和/或乙基纤维素的重量份可为20份、22份、24份、26份、28份或30份等，但并不仅限于所列举的数值，所列范围内其他数值均可行； 所述聚乙二醇的重量份可为10份、12份、14份、16份、18份或20份等，但并不仅限于所列举的数值，所列范围内其他数值均可行；所述溶剂的重量份可为750份、752份、754份、756份、758份或760份等，但并不仅限于所列举的数值，所列范围内其他数值均可行。
优选地，所述溶剂为乙醇、丙酮或水中任意一种或至少两种的组合。
第二方面，本发明提供了上述制备方法制备得到的盐酸二甲双胍渗透泵片，包括盐酸二甲双胍片芯和包裹在盐酸二甲双胍片芯外的控释衣膜，所述盐酸二甲双胍渗透泵片的长径与短径的长度之比为1.2～4，例如1.2、1.3、1.5、1.8、2.0、2.2、2.5、2.8、3.0、3.2、3.5、3.8、3.9或4等，但并不仅限于所列举的数值，所列范围内其他数值均可行，进一步优选为1.5～3，特别优选的为1.8～2.7。
作为本发明优选的技术方案，所述盐酸二甲双胍渗透泵片的形状为非圆形。
优选地，所述盐酸二甲双胍渗透泵片的形状为胶囊形。
优选地，所述盐酸二甲双胍渗透泵片的形状为椭圆形。
与现有技术相比，本发明具有以下有益效果：
本发明所述方法采用异型冲压制盐酸二甲双胍片芯，然后在经过压制的盐酸二甲双胍片芯外包裹控释衣膜制成盐酸二甲双胍渗透泵片。本发明制得的盐酸二甲双胍渗透泵片的片重较小，1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右；并且，制得的盐酸二甲双胍渗透泵片在达到与现有技术相同的控制药物释放效果的前提下，同等重量的渗透泵片的横截面积与传统缓释片剂相比大大降低，甚至可以降低50％以上，使所得的渗透泵片剂更加易于吞咽，极大的提高了病人的顺应性。
附图说明
图1是本发明所述盐酸二甲双胍渗透泵片的形状示意图；
图2是本发明实施例1制备得到的盐酸二甲双胍渗透泵片的释放曲线；
图3是本发明实施例1制备得到的盐酸二甲双胍渗透泵片的释放曲线。
具体实施方式
为更好地说明本发明，便于理解本发明的技术方案，下面对本发明进一步详细说明。但下述的实施例仅仅是本发明的简易例子，并不代表或限制本发明的权利保护范围，本发明保护范围以权利要求书为准。
本发明具体实施例部分提供了一种盐酸二甲双胍渗透泵片及其制备方法，所述制备方法包括以下步骤：
(1)配制粘合剂溶液，将盐酸二甲双胍、片芯辅料与粘合剂溶液进行混合制粒，然后进行干燥和整粒；
(2)经整粒得到的颗粒采用异型冲压制成盐酸二甲双胍片芯；
(3)在制得的盐酸二甲双胍片芯外包裹控释衣膜，得到盐酸二甲双胍渗透泵片。
实施例1：
本实施例中所用各原料的配比如表1所示：
表1：原料配比表
Figure PCTCN2016091933-appb-000004
Figure PCTCN2016091933-appb-000005
(1)按原料配比，将聚维酮K30与95wt％的乙醇混合配成粘合剂溶液；
(2)按原料配比将盐酸二甲双胍与十二烷基硫酸钠和聚山梨醇加入到湿法制粒机中，在搅拌桨转速为75r/min、切刀转速为500r/min的条件下混合3min；然后保持搅拌桨转速不变，提高切刀转速至1000r/min，然后将粘合剂溶液缓慢加入至湿法制粒机中，加入过程约持续1min，得到湿颗粒；
(3)得到的湿颗粒过Quadro Comil整粒机进行湿整粒，然后用流化床进行干燥，干燥过程中，进风温度为50℃，风机频率为20Hz，每隔5min取样测定干燥失重，直至干燥失重值小于1wt％后停止干燥，再经Quadro Comil整粒机进行整粒(0.05in.筛网直径)；
(4)经整粒得到的颗粒与硬脂酸镁在25r/min转速下混合10min后以19x7.9mm的胶囊形冲压制成每片含盐酸二甲双胍1000mg的片芯；
(5)按原来配比将聚乙二醇3350溶于水中得到聚乙二醇3350水溶液，将配方量的醋酸纤维素溶于丙酮中得到醋酸纤维素的丙酮溶液，再将聚乙二醇3350水溶液加入到醋酸纤维素的丙酮溶液中得到包衣液；
(6)使用步骤(5)制得的包衣液对盐酸二甲双胍片芯进行包衣，其中，包衣片床温度40℃，雾化压力0.6Mpa，吹扁压力0.2Mpa，包衣液流速40～45g/min，待包衣增重达到约为5％时停止包衣，放入40℃的烘箱中干燥24h，然后在片芯的两侧均打0.6毫米的释药孔道，得到盐酸二甲双胍渗透泵片。
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为2.4，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低50％，其缓释曲线如图1所示，可以看出所述盐酸二甲双胍渗透泵片在桨法50r/min，pH为6.8的磷酸盐缓冲液中达到与现有技术相同的控制 药物释放效果。
实施例2：
本实施例中所用各原料的配比如表2所示：
表2：原料配比表
Figure PCTCN2016091933-appb-000006
(1)按原料配比，将羟丙甲纤维素E3与水混合配成粘合剂溶液；
(2)按原料配比将盐酸二甲双胍与十二烷基硫酸钠和甘露醇加入到流化床制粒机中，在进风温度为50℃，风机频率为20Hz，雾化压力为0.4Mpa的条件下顶喷制粒，然后加入粘合剂溶液，在相同条件下干燥，每隔5min测定样品的干燥失重，直至干燥失重小与1％后停止干燥，再以Quadro Comil整粒机进行整粒(0.05in.筛网直径)；
(3)经整粒得到的颗粒与硬脂酸镁在25r/min转速下混合10min后以19x7.9mm的胶囊形冲压制成每片含盐酸二甲双胍1000mg的片芯；
(4)按原来配比将聚乙二醇3350溶于水中得到聚乙二醇3350水溶液，将配方量的乙基纤维素溶于无水乙醇中得到乙基纤维素的乙醇溶液，再将聚乙二醇3350水溶液加入到乙基纤维素的乙醇溶液中得到包衣液；
(6)使用步骤(4)制得的包衣液对盐酸二甲双胍片芯进行包衣，其中，包衣片床温度40℃，雾化压力0.6Mpa，吹扁压力0.2Mpa，包衣液流速 40～45g/min，待包衣增重达到约为5％时停止包衣，放入40℃的烘箱中干燥24h，然后在片芯的两侧均打0.6毫米的释药孔道，得到盐酸二甲双胍渗透泵片。
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为2.4，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低50％，其缓释曲线如图2所示，可以看出所述盐酸二甲双胍渗透泵片在桨法50r/min，pH为6.8的磷酸盐缓冲液中达到与现有技术相同的控制药物释放效果。
实施例3：
本实施例中除了所用各原料采用表3中所示的配比，采用19x15.8mm的椭圆形冲，包衣增重达到约为3％时停止包衣外，其他物料用量与制备方法均与实施例1中相同。
表3：原料配比表
Figure PCTCN2016091933-appb-000007
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为1.2，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低40～50％，其可达到与现有技术相同的控制药物释放效果。
实施例4：
本实施例中除了所用各原料采用表4中所示的配比，采用19x4.75mm的椭 圆形冲，包衣增重达到约为8％时停止包衣外，其他物料用量与制备方法均与实施例1中相同。
表4：原料配比表
Figure PCTCN2016091933-appb-000008
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为4，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低40～50％，其可达到与现有技术相同的控制药物释放效果。
实施例5：
本实施例中除了所用各原料采用表5中所示的配比，采用19x7.9mm的椭圆形冲，包衣增重达到约为2.5％时停止包衣外，其他物料用量与制备方法均与实施例1中相同。
表5：原料配比表
Figure PCTCN2016091933-appb-000009
Figure PCTCN2016091933-appb-000010
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为2.4，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低40～50％，其可达到与现有技术相同的控制药物释放效果。
实施例6：
本实施例中除了所用各原料采用表6中所示的配比，采用19x7.9mm的椭圆形冲，包衣增重达到约为10％时停止包衣外，其他物料用量与制备方法均与实施例1中相同。
表6：原料配比表
Figure PCTCN2016091933-appb-000011
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为2.4，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低40～50％，其可达到与现有技术相同的控制药物释放效果。
实施例7：
本实施例中除了采用19x10.6mm的椭圆形冲外，其他物料用量与制备方法均与实施例1中相同。
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为1.8，其横截面积较传统缓释片剂(采用圆形冲 压制)可以降低40～50％，其可达到与现有技术相同的控制药物释放效果。
实施例8：
本实施例中除了采用19x7mm的椭圆形冲外，其他物料用量与制备方法均与实施例1中相同。
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为2.7，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低40～50％，其可达到与现有技术相同的控制药物释放效果。
实施例9：
本实施例中除了采用19x6.3mm的椭圆形冲外，其他物料用量与制备方法均与实施例1中相同。
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为3，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低40～50％，其可达到与现有技术相同的控制药物释放效果。
实施例10：
本实施例中除了采用19x12.7mm的椭圆形冲外，其他物料用量与制备方法均与实施例1中相同。
本实施例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为1.5，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低40～50％，其可达到与现有技术相同的控制药物释放效果。
实施例11：
本实施例中除了步骤(6)包衣后的片芯两侧不制备释药孔道外，其他物料用量与制备方法均与实施例1中相同。
本实例制得的1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右，长径与短径的长度之比为2.4，其横截面积较传统缓释片剂(采用圆形冲压制)可以降低50％。
综合实施例1-11的结果可以看出，本发明所述方法采用异型冲压制盐酸二甲双胍片芯，然后在经过压制的盐酸二甲双胍片芯外包裹控释衣膜制成盐酸二甲双胍渗透泵片。本发明制得的盐酸二甲双胍渗透泵片的片重较小，1000mg规格的盐酸二甲双胍渗透泵片，其片重仅为1.2g左右；制得的盐酸二甲双胍渗透泵片在达到与现有技术相同的控制药物释放效果的前提下，同等重量的渗透泵片的横截面积与传统缓释片剂相比大大降低，甚至可以降低50％以上，使所得的渗透泵片剂更加易于吞咽，极大的提高了病人的顺应性。
申请人声明，本发明通过上述实施例来说明本发明的详细方法，但本发明并不局限于上述详细方法，即不意味着本发明必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。

Claims (10)

  1. 一种盐酸二甲双胍渗透泵片的制备方法，其特征在于，所述制备方法为：采用异型冲压制盐酸二甲双胍片芯，在经过压制的盐酸二甲双胍片芯外包裹控释衣膜制成盐酸二甲双胍渗透泵片。
  2. 根据权利要求1所述的制备方法，其特征在于，所述方法包括以下步骤：
    (1)配制粘合剂溶液，将盐酸二甲双胍、片芯辅料与粘合剂溶液进行混合制粒，然后进行干燥和整粒；
    (2)经整粒得到的颗粒采用异型冲压制成盐酸二甲双胍片芯；
    (3)在制得的盐酸二甲双胍片芯外包裹控释衣膜，得到盐酸二甲双胍渗透泵片。
  3. 根据权利要求1或2所述的制备方法，其特征在于，所述异形冲为胶囊形冲或椭圆形冲；
    优选地，采用异型冲时，控制盐酸二甲双胍片芯的长径与短径的长度之比为1.2～4，进一步优选为1.5～3，特别优选为1.8～2.7；
    优选地，所述盐酸二甲双胍渗透泵片外包裹的控释衣膜上制备有释药孔道；
    优选地，所述释药孔道的个数≥1。
  4. 根据权利要求1-3任一项所述的制备方法，其特征在于，盐酸二甲双胍片芯包裹控释衣膜后，以片芯重量计，控释衣膜增重≥2wt％，进一步优选为2.5～10wt％，特别优选为3～8wt％。
  5. 根据权利要求2-4任一项所述的制备方法，其特征在于，步骤(1)配制粘合剂溶液为：将粘合剂与溶剂混合配制成粘合剂溶液；
    优选地，所述粘合剂为聚维酮、羟丙甲纤维素或羟丙基纤维素中任意一种或至少两种的组合；
    优选地，所述溶剂为纯度为95wt％的乙醇和/或水；
    优选地，所述粘合剂为聚维酮，溶剂为纯度为95wt％的乙醇时，聚维酮与纯度为95wt％的乙醇的质量比为(10～15)∶(90～85)，进一步优选为15∶85；
    优选地，所述粘合剂为羟丙甲纤维素，溶剂为水时，羟丙甲纤维素与水的质量比为(10～15)∶(290～285)，进一步优选为15∶285。
  6. 根据权利要求2-5任一项所述的制备方法，其特征在于，步骤(1)中所述片芯辅料包括十二烷基硫酸钠和填充剂；
    优选地，所述填充剂为聚山梨醇、山梨醇或甘露醇中任意一种或至少两种的组合；
    优选地，步骤(1)中粘合剂溶液、盐酸二甲双胍、十二烷基硫酸钠和填充剂按如下重量份进行混合：
    Figure PCTCN2016091933-appb-100001
    优选地，步骤(1)中粘合剂溶液、盐酸二甲双胍、十二烷基硫酸钠和聚山梨醇按如下重量份进行混合：
    Figure PCTCN2016091933-appb-100002
    优选地，步骤(1)中粘合剂溶液、盐酸二甲双胍、十二烷基硫酸钠和甘露 醇按如下重量份进行混合：
    Figure PCTCN2016091933-appb-100003
  7. 根据权利要求2-6任一项所述的制备方法，其特征在于，步骤(1)所述整粒过程中加入润滑剂；
    优选地，所述润滑剂为硬脂酸镁；
    优选地，所述润滑剂的加入量为盐酸二甲双胍质量的0.5～1％。
  8. 根据权利要求1-7任一项所述的制备方法，其特征在于，所述包裹控释衣膜过程中所用的包衣液包括控释材料和致孔剂；
    优选的，所述控释材料为醋酸纤维素和/或乙基纤维素；
    优选地，所述致孔剂为聚乙二醇；
    优选地，所述包衣液主要由以下组分按重量份计组成：
    控释材料                  20～30份
    致孔剂                    10～20份
    溶剂                      750～760份；
    优选地，所述溶剂为乙醇、丙酮或水中任意一种或至少两种的组合。
  9. 根据权利要求1-8任一项所述的制备方法制备得到的盐酸二甲双胍渗透泵片，包括盐酸二甲双胍片芯和包裹在盐酸二甲双胍片芯外的控释衣膜，其特征在于，所述盐酸二甲双胍渗透泵片的长径与短径的长度之比为1.2～4，进一步优选为1.5～3，特别优选的为1.8～2.7。
  10. 根据权利要求9所述的盐酸二甲双胍渗透泵片，其特征在于，所述盐酸二甲双胍渗透泵片的形状为非圆形；
    优选地，所述盐酸二甲双胍渗透泵片的形状为胶囊形；
    优选地，所述盐酸二甲双胍渗透泵片的形状为椭圆形。
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