WO2008089593A1 - Preparation de tamsulosine a liberation prolongee et procede de production associe - Google Patents

Preparation de tamsulosine a liberation prolongee et procede de production associe Download PDF

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Publication number
WO2008089593A1
WO2008089593A1 PCT/CN2007/000200 CN2007000200W WO2008089593A1 WO 2008089593 A1 WO2008089593 A1 WO 2008089593A1 CN 2007000200 W CN2007000200 W CN 2007000200W WO 2008089593 A1 WO2008089593 A1 WO 2008089593A1
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Prior art keywords
tamsulosin
dosage form
sustained release
cellulose
release dosage
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PCT/CN2007/000200
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English (en)
French (fr)
Inventor
Ching-Fen Hsiao
Sung-Jen Chen
Ya-Ching Chang Chien
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Standard Chem. & Pharm. Co., Ltd.
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Priority to PCT/CN2007/000200 priority Critical patent/WO2008089593A1/zh
Publication of WO2008089593A1 publication Critical patent/WO2008089593A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate

Definitions

  • the present invention relates to a Tamsulosin sustained release dosage form and a method of manufacture. Background technique
  • Tamsulosin is used to treat benign prostatic hyperplasia (BPH), which is characterized by hyperplasia of the prostate tissue.
  • the new mechanism of action of tamsulosin is to reduce the pressure of the prostate in the urethral pressure curve by blocking the urethra and the ⁇ -acceptor of the prostate, and to improve the urinary dysfunction associated with prostatic hypertrophy.
  • Tansulosin is also known as 5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxy-benzenesulfonamide (5-[2- [[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxy- benzenesulfonamide).
  • EP34432 and U.S. Patent No. 4,731,4708 the activity of tamsulosin having an ⁇ -adrenergic blocker, which can be used for the treatment of heart disease and benign prostatic hyperplasia, has been separately disclosed.
  • a controlled release dosage form comprising a plurality of particles comprising tamsulosin, microcrystalline cellulose and a release controlling agent is mentioned in U.S. Patent No. 4,477,475.
  • the release controlling agent comprises an acrylic polymer, an acrylic copolymer or a cellulose derivative which is made higher than 50 ° /.
  • the (w/w) microcrystalline cellulose is added to an oral sustained release agent as a dry release regulator.
  • the particles are gradually released from the particle matrix of tamsulosin.
  • This patent suggests that no enteric coating is required.
  • high concentrations of microcrystalline cellulose will increase the temperature of the granulation process for making controlled release dosage forms.
  • the acrylic polymer forms a gel at high temperatures and is detrimental to the manufacturing process.
  • a method of making the aforementioned granules comprises forming a mixture comprising tamsulosin into granules, adding microcrystalline cellulose and a controlled release dosage form comprising water and/or a liquid emulsifier to the granule, to be water insoluble macromolecules
  • the gum or suspension coats the particles.
  • the large component is preferably selected from the group consisting of acrylic polymers.
  • the controlled release agent can be used as an adhesive in the particle formation process. Obtained
  • the granules can be used as capsules or lozenges.
  • U.S. Patent No. 4,772,475 describes various particle compositions and their release characteristics are tested by the standardized method described in the Pharmacopoeia (150 rpm agitation). The results reported show that the active substance is released in the range of 16.2% to 60.4% in 1 hour under gastric juice.
  • the traditional lozenges and the lozenges of the case were measured in the plasma of the volunteers, respectively, to a concentration of 50.3% to 57.6% of the active substance.
  • the tablet dose reached a peak plasma concentration about 3 hours after taking it (about 2 hours compared with the conventional tablet), and the total dose in plasma was about 75% of the conventional tablet.
  • the present invention provides a sustained release dosage form comprising Tamsulosin comprising an effective amount of tamsulosin or a pharmaceutically acceptable salt thereof, 10% to 50% (w/w) cellulose
  • the hydrophobic polymer compound is used as a release rate regulator and 10%-30. /. (w/w) round granule forming agent with 30%-50. /o(w/w) diluent, and the sum of the components is 100%.
  • the sustained release dosage form of the present invention can dry release less than 5% of tamsulosin or a pharmaceutically acceptable salt thereof during the first two hours of the in vitro dissolution test.
  • the diluent contained in the sustained release dosage form is lactose, starch, mannitol, sodium carboxymethylcellulose, sodium starch, microcrystalline cellulose, talc, stearic acid, stearate, and corydalis.
  • the cellulose-based hydrophobic polymer compound contained in the sustained-release dosage form is an acid-base-related cellulose or a non-acid-base-related cellulose.
  • the cellulose-based hydrophobic polymer compound contained in the sustained release dosage form is a methacrylic acid polymer, sodium carboxymethyl cellulose (sodium CMC), cellulose acetate, and ethyl cellulose (EC). ), carboxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), co-processed polyvinyl acetate phthalate, benzodiazepine acetate Crystalline cellulose (CAP) or a combination thereof.
  • methacrylic acid polymer sodium carboxymethyl cellulose (sodium CMC), cellulose acetate, and ethyl cellulose (EC).
  • HPMCP carboxypropyl methylcellulose phthalate
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • CAP benzodiazepine acetate Crystalline cellulose
  • the round granule forming agent contained in the sustained release dosage form is a glyceride or a waxy substance.
  • the round granule forming agent contained in the sustained release dosage form is glyceryl triacetate ⁇ glyceryl monostearate, glyceryl behenate, Shi Zeng ( Paraffin wax), palmauba wax or a combination thereof.
  • the sustained release dosage form contains tamsulosin in an amount of 0.01% of the sustained release dosage form -
  • the sustained release dosage form contains tamsulosin in an amount of 0.03% of the sustained release dosage form -
  • the present invention further provides a method for producing a sustained release dosage form with tamsulosin comprising: an effective amount of water-soluble tamsulosin or a pharmaceutically acceptable salt thereof, a granule forming agent, a release rate
  • the conditioning agent and diluent are mixed to form a mixture; a film coat premix is prepared; the mixture is granulated and the film coat premix is coated onto the granules.
  • the film coat premix is soluble in water or an organic solvent.
  • the dry release rate controlling agent is a cellulose-based hydrophobic polymer compound.
  • the hydrophobic polymer compound is a methacrylic acid polymer, sodium carboxymethyl cellulose, cellulose acetate, ethyl cellulose, carboxypropyl methyl cellulose phthalic acid. Salt, hydroxypropyl methyl-cellulose acetate succinate, co-processed polyvinyl acetate Phthalate) phthalic acid microcellulose or a combination thereof.
  • the pellet former is triacetin, glyceryl stearate, oleic acid ester, paraffin wax, palm wax or a combination thereof.
  • the film coat premix is comprised of one or more ethyl cellulose, triethyl citrate, methacrylic acid polymer, talc, or a combination thereof.
  • Figure 1 is a graph of time versus plasma drug concentration according to Tables 1 and 2.
  • Figure 2 is a graph of time versus plasma drug concentration according to Tables 3 and 4.
  • Figure 3 is a graph of time versus plasma drug concentration according to Tables 5 and 6. detailed description
  • the present invention provides a new tamsulosin sustained release dosage form comprising tamsulosin and a pharmaceutically acceptable salt thereof, about 10% to about 50% (w/w) of a hydrophobic polymer compound, about 10% to about 30% (w/w) of a round granule forming agent, and about 30% to 50% (w/w) of a diluent, if necessary, the slow-drying dosage form may further selectively include other according to actual needs.
  • Component for example, an appropriate amount of a plasticizer or the like, and the sum of the components is 100%.
  • the sustained release dosage form releases less than 5% of tamsulosin or a pharmaceutically acceptable salt thereof during the first two hours of the in vitro dissolution test.
  • tamsulosin new sustained release dosage form as used herein means that the fommlation or dosage obtained according to the present invention can be slowly and gradually released and absorbed in the gastrointestinal tract for a period of time after administration to a user. .
  • the "round granule forming agent" as used herein means an adhesive which can be applied to the formation of granules of the present invention. According to the present invention, the pellet forming agent can be simultaneously used to make the pellet size uniform.
  • the "fluctuation" referred to in the present invention means a new concentration of tamsulosine in the human body. Small fluctuations indicate a new concentration of tamsulosin in the human body, such as plasma.
  • the invention further provides a method for producing a new sustained release dosage form of tamsulosin, which comprises an effective amount 00200 of water-soluble tamsulosin or a pharmaceutically acceptable salt thereof, a granule forming agent, a release rate regulator, and a diluent are mixed to form a mixture; a film-coat premix is prepared; the mixture is granulated, The film coat premix is coated onto the granules.
  • an effective, modified tamsulosin new sustained release dosage form can be obtained, and the obtained sustained release dosage form has a stable controlled release rate profile.
  • the release rate of tamsulosin it is found that in the in vitro dissolution test, it can be measured at a rotational speed of 50 rpm, simulated gastric juice stimulation, within the first two hours after administration. Less than 5% released amount of tamsulosin or a pharmaceutically acceptable salt thereof. Therefore, when the tamsulosin new sustained release dosage form of the present invention is administered, the release rate of tamsulosin can be lowered in the stomach of the user.
  • the tamsulosin new sustained release dosage form is a granule.
  • the particle size, composition, and coating amount of the particles cause the particles to exhibit the following changes in plasma concentration in the human body: the concentration of the drug in plasma is about 1 ng of tamsulosin/ml plasma within 2 hours, in plasma within 4 hours.
  • the drug concentration was approximately 3 ng of tamsulosin/ml plasma, and the plasma drug concentration was approximately 4 ng of tamsulosin/ml plasma within 6 hours.
  • the new tamsulosin sustained release dosage form according to the present invention shows a stable release rate regardless of whether it is after eating or in a fasting state.
  • hydrophobic polymer compound (hydrophobic polymer) is suitably used as a sustained-release dosage form, and includes an acid-base-related cellulose and a non-acid-reduced cellulose.
  • a hydrophobic polymer compound (an acid-base-related cellulose and a non-acid-base related cellulose) can be used for controlling a new sustained release dosage form of tamsulosin.
  • the release rate therefore, the new tamsulosin sustained release dosage form disclosed herein can be released slowly and stably in the gastrointestinal tract.
  • the new release rate of tamsulosin is too fast, it will result in dose dumping effects, so the controlled release ability of the polymer is very important for sustained release dosage forms.
  • the hydrophobic polymer compound used in accordance with the present invention is a type which has a function of avoiding a burst-out function which suddenly occurs in the gastrointestinal tract after administration of a drug.
  • Many known in the pharmaceutical field Hydrophobic compound including but not limited to, methacrylic acid polymer, sodium carboxymethyl cellulose (sodium CMC), cellulose acetate, ethyl cellulose (EC), carboxypropyl methyl benzoquinone Acidate (HPMCP), hydroxypropyl methyl-cellulose acetate succinate, co-processed polyvinyl acetate phthalate or benzoic acid cellulose (CAP) .
  • the aforementioned hydrophobic polymer compound may be used singly or in combination.
  • the acid-base related polymer used in the present invention is used in an amount of about 10% to 50% (w/w).
  • a water soluble tamsulosin, a pellet forming agent, a release controlling agent and a diluent are mixed to form a mixture.
  • the mixture is dissolved in a suitable solvent, and the prepared refining liquid is subjected to wet granulation to delay the release rate of the drug.
  • the pellet former used in the present invention to form round grains may preferably be a glyceride or a paraffin wax.
  • the release controlling agent used in the present invention to control the delayed release rate is preferably a hydrophobic polymer compound.
  • the mixed mixture is added to a knead solution to form an oral pellet.
  • the tamsulosin new sustained release dosage form of the present invention is orally rounded, and if necessary, the mixture or granules can be refilled in a hard capsule. If necessary, one or more layers of differently acting film coats may be applied to the surface of the particles for different purposes.
  • the amount of tamsulosin and its pharmaceutically acceptable salt is from about 0.03% to about 3% (w/w).
  • the concentration of the hydrophobic polymer compound is about 10% to 50°/. (w/w).
  • the hydrophobic polymer compound can be used to reduce the amplitude of the sustained release dosage form in the human body.
  • the round granule forming agent contained at the same time can be used as a lubricant to promote a smoother process for producing the granules. Therefore, the gel state of the acrylic polyol polymer at a high temperature can be improved by using a round granule forming agent.
  • a pharmaceutically acceptable diluent may be contained at the same time.
  • the diluent is used in an amount of from about 30% to about 50% (w/w).
  • the diluent is used in an amount of from about 30% to about 40% (w/w).
  • the diluent can be lactose, starch, mannitol, carboxymethyl N2007/000200 sodium sulphate sodium, sodium starch, microcrystalline cellulose, talc, stearic acid, stearate, stearyl fomarate, glyceryl behenate Or a combination thereof.
  • a preferred round granule forming agent may be glyceryl triacetate ⁇ glyceryl monostearate, glyceryl behenate, paraffin wax , carnauba wax or a combination thereof.
  • the film coat used in the present invention and a method for producing the same are well known to those having ordinary knowledge in the art.
  • the film coat premix can be first dissolved in water or an organic solvent.
  • the organic solvent used to prepare the film coat premix may be ethanol, acetone, isopropyl alcohol or a mixed solvent thereof, and if necessary, may contain other diluents, plasticizers or anti-adhesive agents, dissolved or dispersed in the above solution.
  • Example 1 Formulation and preparation method of tamsulosin new sustained release dosage form (1)
  • Triethyl citrate 10.8 g weight
  • the main component of tamsulosin hydrochloride, polyvinyl acetate phosphate, microcrystalline cellulose, two Dodecanoic acid glycerides and the like are uniformly mixed to obtain a mixture.
  • Ethyl cellulose was wet-mixed and added to the above mixture, and granulated by an extrusion granulator or a centrifugal pulverizer.
  • the dried pellets are placed in a fluidized layer granulator, and the film coating premix is dissolved in a suitable solvent and sprayed onto the surface of the pellet.
  • Example 1 the round particles obtained in Example 1 were filled in a plastic capsule, and then six adult males were fed and fasted in a crossover method. In the state of administration. After appropriate intervals, the subject's blood is drawn and the concentration of tamsulosin in the plasma is measured using a plausible analytical method. The data shows that the new tamsulosin sustained release dosage form disclosed herein is very stable.
  • Example 1 The new tamsulosin sustained-release dosage form obtained in Example 1 was administered to six adult males. In the satiety state, the average plasma tamsulosin concentration was
  • Table 2 the new tamsulosin sustained-release dosage form obtained in Example 1, was administered to six adult males in a fasting state, and the average plasma tamsulosin concentration was
  • Example 2 Formulation and preparation of tamsulosin new sustained release dosage form (2)
  • Tansolo new hydrochloride 1.60 g weight
  • Ethylcellulose and triethyl citrate are wet-mixed, then added to the above mixture, and granulated by a bridge granulator or a centrifugal rounding machine.
  • the dried pellets are placed in a fluidized layer granulator, and the film coat premix is dissolved in a suitable solvent and sprayed onto the surface of the pellet. .
  • Example 2 the round particles obtained in Example 2 were filled in a plastic capsule, and then six adult males were given a crossover method in a satiety and fasting state, respectively. Dosing. After appropriate intervals, the subject's blood is drawn and the concentration of tamsulosin in the plasma is measured using a plausible analytical method. The data shows that the new tamsulosin sustained release dosage form disclosed herein is very stable.
  • Table 4 the new tamsulosin sustained-release dosage form obtained in Example 2, administered to six adult males in the fasting state, the average plasma tamsulosin concentration
  • Example 3 Release rate test with traditional tamsulosin new sustained release dosage form
  • the traditional tamsulosin new sustained-release dosage form (trade name: Flomax (Boehringer Ingelheim)) is given to six adulthoods by cross over method. Men were given medications in a satiety and fasting state. After an appropriate time interval, the subject's blood is drawn and the concentration of tamsulosin in the plasma is measured using a plausible analytical method. The data show that in the satiety state and the fasting state, the traditional tamsulosin new sustained release dosage form has two different areas under the curve. Therefore, the traditional tamsulosin sustained-release dosage form has a slow release effect.
  • the tamsulosin new sustained release dosage form of the present invention has the following distinct advantages:
  • the new tamsulosin sustained release dosage form disclosed in the present invention surprisingly exhibits results unaffected by food. Therefore, it is possible to safely administer the drug before or after the meal, without being restricted by food.

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Description

坦索洛新緩释剂型及制造方法 技术领域
本发明是有关坦索洛新 (Tamsulosin)緩释剂型及制造方法。 背景技术
坦索洛新（Tamsulosin)是用于治疗良性前列腺增生（benign prostatic hyperplasia; BPH), 该疾病的特征在于前列腺体组织会有增生的现象。
坦索洛新作用机理是经由阻断尿道及前列腺部 α-接受体， 致使尿道内 压曲线的前列腺部压降低， 而改善前列腺肥大症所伴随的排尿障碍。
坦索洛新又称为 5-[2-[[2-(2-乙氧基苯氧）乙基]胺基]丙基] -2-甲氧基-苯 磺酰胺 (5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxy- benzenesulfonamide)。 欧洲专利 EP34432号及美国专利 US4731478号中， 已分别揭露坦索洛新具有 α -肾上腺素阻滞剂的活性， 其可用于治疗心脏病 及良性前列腺增生。
在美国专利 US477475 号中提及控释剂型， 该剂型包含多个含有坦索 洛新、 微结晶纤维素及释放控制剂的颗粒。 该释放控制剂包含丙烯酸聚合 物、 丙烯酸共聚物或纤维素衍生物， 其是使高于 50°/。(w/w)的微结晶纤维 素加入一口服型緩释剂中以作为幹放调节剂。 该颗粒是自颗粒基质中逐渐 释放出坦索洛新。 该专利建议不需使用肠膜衣。 然而， 高浓度的微结晶纤 维素将使得制造控释剂型的成粒 (granulation)过程温度升高。 同时， 在高温 下丙烯酸聚合物会形成胶状而对制造过程不利。
已有制造前述颗粒的方法包含， 将含有坦索洛新的混合物形成颗粒 , 使微结晶纤维素及包含水和 /或液态乳化剂的控释剂型加入该颗粒中， 以非 水溶性大分子的胶状物或悬浮液包覆该颗粒。 该大分乎 质优选是选自丙 烯酸聚合物。 同时， 该控释剂在颗粒形成过程可作为粘着剂使用。 所得到 的颗粒可以用为胶嚢或锭剂。
在美国专利 US477475 号的实施例一中， 叙述了其制造流程。 在混合 5无坦索洛新及 470克的微结晶纤维素后， 将 83克 Eudragit L30 D-55及 500 克水所形成的混合物加入前述混合物， 而后在高速混合机中制粒。 所 得颗粒的粒径为 0.1 nun至 1.5mm, 主要为 0.2mm至 1.0mm。
美国专利 US4772475号同时描述了多种颗粒组合物， 并以药典所记载 的标准化方法 (150rpm搅拌)测试其释放特性。 所记载的结果显示在胃液 下， 1 小时可释放活性物质的范围为 16.2%至 60.4%。 传统锭剂与该案的 锭剂在自愿受试者的血浆则可分别测得 50.3%至 57.6%活性物质浓度。 该 案的锭剂约在服用后 3小时可达血浆浓度的高峰 (相较于传统锭剂则在 2小 时左右）， 在血浆中的总剂量约为传统锭剂的 75%。
然而， 这种释放速率仍然不足以形成持续幹放剂。 因此， 亟需一种可 以混合均匀同时于制造过程中可克服工艺中的高温及不易制粒的问题， 而 使制造的药物可以具有稳定的药效， 达到持续释放效果的坦索洛新 (Tamsulosin)活性物质的医药组合物， 使该組合物维持原活性物盾的药理学 特性， 以供病人使用。 发明内容
本发明提供了一种含有坦索洛新 (Tamsulosin)的緩释剂型， 其包括有效 量的坦索洛新或其医药上可接受的盐类、 10%-50%(w/w)纤维素类疏水性高 分子化合物作为释放速率调控剂及 10%-30。/。(w/w)圆粒形成剂与 30%- 50。/o(w/w)稀释剂， 且各組分之和为 100%。 本发明的緩释剂型可在体外溶 离试验最初的二小时内幹放出少于 5%的坦索洛新或其医药上可接受的盐 类。
优选的是， 该緩释剂型所含稀释剂为乳糖、 淀粉、 甘露醇、 羧甲基纤 维素钠、 淀粉钠、 微结晶纤维素、 滑石粉、 硬酯酸、 硬酯酸盐、 延胡索硬 酯酸钠、 二十二酸甘油酯或其组合。
优选的是， 该緩释剂型所含的纤维素类疏水性高分子化合物为酸碱相 关性的纤维素或非酸碱相关性的纤维素。
优选的是， 该緩释剂型所含的纤维素类疏水性高分子化合物为异丁烯 酸聚合物、 羧甲基纤维素钠 (sodium CMC)、 醋酸纤维素 (cellulose acetate)、 乙基纤维素 (EC)、 羧丙基甲基纤维苯二甲酸盐 (HPMCP)、 羟丙甲基纤维素 醋酸琥珀酸酯（HPMCAS)、 聚醋酸乙浠磷酸盐（co-processed polyvinyl acetate phthalate), 乙酸苯二微结晶纤维素 (CAP)或其组合。
优选的是， 该緩释剂型所含的圆粒形成剂为甘油酯类或蜡质物质。 优选的是， 该緩释剂型所含的圆粒形成剂为甘油三醋酸酯 (glyceryl triacetate) ^ 肯油硬脂酸酯 (glyceryl monostearate)、 二十二酸甘油酯 (glyceryl behenate)、 石增 (paraffin wax)、 棕榈措 (carnauba wax)或其组合。
优选的是， 该緩释剂型所含的坦索洛新的含量占緩释剂型的 0.01%-
Figure imgf000005_0001
更优选的是， 该緩释剂型所含的坦索洛新的含量占緩释剂型的 0.03%-
3%(w/w)。
本发明另提供了一种舍有坦索洛新的緩释剂型的制造方法， 包括： 将 有效量的水溶性坦索洛新或其医药上可接受的盐类、 圆粒形成剂、 释放速 率调控剂及稀释剂加以混合以形成混合物； 预备一膜衣预混物； 将混合物 制成颗粒， 将膜衣预混物包覆于颗粒上。
优选的是， 该膜衣预混物可溶解于水或有机溶剂。
优选的是， 该幹放速率调控剂为纤维素类疏水性高分子化合物。
优选的是， 该緩释剂型制造方法中， 疏水性高分子化合物为异丁烯酸 聚合物、 羧甲基纤雉素钠、 醋酸纤维素、 乙基纤维素、 羧丙基甲基纤维苯 二甲酸盐、 羟丙甲基纤维素醋酸琥珀酸酯 (hydroxypropyl methyl-cellulose acetate succinate)、 聚醋酸乙締磚酸盐 (co-processed polyvinyl acetate phthalate)^ 乙酸苯二微结晶纤维素或其組合。
优选的是， 圓粒形成剂为甘油三醋酸酯、 甘油硬脂酸酯、 二十二酸甘 油酯、 石蜡、 棕榈蜡或其组合。
优选的是， 膜衣预混物是由一种或多种乙基纤维素、 柠檬酸三乙酯、 异丁烯酸聚合物、 滑石粉或其組合所组成。 附图说明
图 1为根据表一及表二以时间对血浆中药物浓度所作曲线图。
图 2为根据表三及表四以时间对血浆中药物浓度所作曲线图。
图 3为根据表五及表六以时间对血浆中药物浓度所作曲线图。 具体实施方式
本发明提供了一种坦索洛新緩释剂型 , 其包含坦索洛新及其医药上可 接受的盐类、 约 10%至约 50%(w/w)的疏水性高分子化合物、 约 10%至约 30%(w/w)的圆粒形成剂、 及约 30%至 50%(w/w)的稀释剂， 必要时该緩幹 剂型中还可根据实际需要进一步选择性包含其他组分， .例如适量的可塑剂 等， 且各组分之和为 100%。 其中该緩释剂型在体外溶离试验的最初二小 时内释放出少于 5%的坦索洛新或其医药上可接受的盐类。
本发明所指的 "坦索洛新緩释剂型" 在此意指根据本发明所得的调和 物 (fommlation)或剂量， 在给予使用者后可緩慢且逐渐地在一段时间内在肠 胃道释放及吸收。
本发明所指的 "圆粒形成剂" 在此意指可应用于本发明形成颗粒时的 粘着剂。 根据本发明该圆粒形成剂同时可用于使圓粒大小均匀。
本发明所指的 "震荡幅度 (fluctuation)" 在此意指人体内坦索洛新浓度 变化。 较小的波动表示人体内， 例如血浆， 其坦索洛新浓度较为稳定。
本发明另提供了一种制造坦索洛新緩释剂型的方法， 其包含将有效量 00200 的水溶性坦索洛新或其医药上可接受的盐类、 圆粒形成剂、 释放速率调控 剂及稀释剂加以混合以形成混合物； 预备一膜衣预混物； 将混合物制成颗 粒， 将膜衣预混物包覆于颗粒上。
根据本发明可获取一有效、 经修饰的坦索洛新緩释剂型， 所获取的緩 释剂型具有稳定的控制释放速率曲线图 (profile)。 在本发明优选具体实施例 中， 当测量坦索洛新的释放速率时， 发现在体外溶离试验时， 将可在转速 为 50rpm、 仿真胃液刺激下， 在投药后最初的二小时内测量到少于 5%释 放量的坦索洛新或其医药上可接受的盐类。 因此， 当服用本发明的坦索洛 新緩释剂型时， 在服用者胃中将可降低坦索洛新的释放速率。 优选的是， 在本发明优选具体实施例中， 坦索洛新緩释剂型为颗粒。 颗粒的粒径、 组 成物质及膜衣包覆量使颗粒在人体内展现下列的血浆中浓度变化： 在 2小 时内血浆中药物浓度约 lng坦索洛新 /ml血浆， 在 4小时内血浆中药物浓 度约 3ng坦索洛新 /ml血浆， 及在 6小时内血浆中药物浓度约 4ng坦索洛 新 /ml血浆。
优选的是， 根据本发明所揭露的坦索洛新緩释剂型， 显示不论在进食 后或空腹状态皆有稳定的释放速率。
聚合物一般是广泛用于作为緩释剂型的基质。 疏水性高分子化合物 (疏水性聚合物）适合作为緩释剂型使用， 包含酸碱相关性的纤维素及非 酸减相关性的纤维素。
根据本发明所揭露的坦索洛新緩释剂型， 疏水性高分子化合物 (含酸碱 相关性的纤维素及非酸碱相关性的纤维素)， 可用于控制坦索洛新緩释剂型 的释放速率， 因此本发明所揭露的坦索洛新緩释剂型可以緩慢且稳定而持 续的在肠胃道释放。 当坦索洛新释放速率过快时， 将导致突释效应 (dose dumping effects), 因此聚合物的控制释放能力对緩释剂型是十分重要的。
根据本发明所使用的疏水性高分子化合物， 是具有避免药物服用后会 在肠胃道突然产生高量药物 (burst-out)功能的种类。 许多在药学领域已知的 疏水性化合物， 包含但不限于， 异丁烯酸聚合物、 羧甲基纤维素钠 (sodium CMC)^ 醋酸纤维素 (cellulose acetate)> 乙基纤维素 (EC)、 羧丙基甲基纤维 苯二曱酸盐（HPMCP)、 羟丙曱基纤维素醋酸琥珀酸酯（hydroxypropyl methyl-cellulose acetate succinate) 、 聚醋酸乙烯碌酸盐 (co-processed polyvinyl acetate phthalate)或乙酸苯二微结晶纤维素 (CAP)。 在本发明的坦 索洛新緩释剂型中， 可以单独使用或共同使用前述疏水性高分子化合物.。 本发明所使用的酸碱相关性聚合物， 使用量约为 10%至 50%(w/w)。
为制备本发明的坦索洛新緩释剂型， 是将水溶性的坦索洛新、 圆粒形 成剂、 释放控制剂及稀释剂混合以形成混合物。 将混合物溶于适当溶剂 中， 所调配成的炼合液， 进行湿式制粒， 以延緩药物释放速率。
用于本发明以形成圆粒的圆粒形成剂， 优选可为甘油酯或石蜡。 用于 本发明以控制延迟释放速率的释放控制剂， 优选可为疏水性高分子化合 物。 将混合后的混合物加入炼合 (knead)溶液中以形成口服圆粒。 本发明的 坦索洛新緩释剂型口服圆粒， 必要时该混合物或颗粒， 可再充填在硬胶嚢 内。 必要时可在颗粒表面被覆一层或多层不同作用的膜衣， 用以达到不同 的用药目的。
在本发明坦索洛新緩释剂型中， 所含坦索洛新及其医药上可接受的盐 类的量约为 0.03%至约 3%(w/w)。 在本发明坦索洛新緩释剂型中， 所含的 疏水性高分子化合物浓度约为 10%至 50°/。(w/w)。 疏水性高分子化合物可 用于降低緩释剂型在人体内的震荡幅度。 在本发明坦索洛新緩释剂型中， 所含的圆粒形成剂同时可作为润滑剂， 以促进圆粒制造过程可更为顺畅。 因此， 由于丙烯酸多元醇聚合物在高温下所导致的胶状状态， 可藉由使用 圆粒形成剂而改善。
在本发明坦索洛新緩释剂型中， 同时可含有药学上可接受的稀释剂。 稀释剂的用量约为 30%至约 50%(w/w)。 优选的是， 稀释剂的用量约为 30%至约 40%(w/w)。 优选的是， 稀幹剂可为乳糖、 淀粉、 甘露醇、 羧甲基 N2007/000200 歼维素钠、 淀粉钠、 微结晶纤维素、 滑石粉、 硬酯酸、 硬酯酸盐、 延胡索 硬西旨酸 ] (sodium stearyl fomarate)、 二十二酸甘油酯 (glyceryl behenate)或其 组合。
在本发明中， 优选的圆粒形成剂可为甘油三醋酸酯（glyceryl triacetate) ^ 甘油硬月旨酸酉旨 (glyceryl monostearate)、 二十二酸甘油醋 (glyceryl behenate)、 石蜡 (paraffin wax)、 標榈惜 (carnauba wax)或其组合。
关于本发明所使用的膜衣及其制作方法， 对于所属领域中具有通常知 识的人员来说是显而易知的。 举例而言， 膜衣预混物可先溶于水中或有机 溶剂中。 用于制作膜衣预混物的有机溶剂可为乙醇、 丙酮、 异丙醇或其混 合溶媒， 必要时可含有其它稀释剂、 可塑剂或抗粘剂， 溶于或分散于上项 溶液中。
本发明其它的特征及优点将可明显见于下列优选具体事实。
实例
下列实施例用于示范说明本发明。 这些实施例不以任何方式意欲限制 本发明的范围， 但用于指示如何实施本发明的材料及方法。
实施例 1: 坦索洛新緩释剂型的配方与制法 (一）
(a) 坦索洛新盐酸盐 4.90克重
聚醋酸乙烯磷酸盐 480.0克重
微结晶纤维素 (MC) 1080.5克重
二十二酸甘油酯 631.1克重
乙基纤维素 444.0克重
(b) 膜衣
乙基纤维素 150.0克重
柠檬酸三乙酯 10.8克重
调配：
1.将主成分坦索洛新盐酸盐、 聚醋酸乙烯磷酸盐、 微结晶纤维素、 二 十二酸甘油酯等混合均匀， 以获取混合物。
2. 乙基纤维素湿式混合并加入上述混合物中， 以挤压造粒机、 离心搓 圆机进行造粒。
3. 将所得圆粒干燥。
4. 将包含乙基纤维素及柠檬酸三乙酯的膜衣预混物加以混合。
5.将干燥后的圆粒放在流动层造粒机， 并将膜衣预混物溶解于适当溶 剂后， 喷洒于圆粒表面。
. 请参阅图 1及表一与表二所示， 将实施例 1所获取的圆粒填充于胶嚢 内， 而后以交叉试验方式 (cross over method) , 给予六个成年男性分别在饱 食及空腹状态下投药。 在适当时间间隔后， 抽取受试者血液并利用可信的 分析方法测量血浆中坦索洛新的浓度。 数据显示本发明所揭露的坦索洛新 緩释剂型十分稳定。
表一、 由实施例 1所获取的坦索洛新緩释剂型， 投药给六个成年男性 在饱食状态下， 其平均血浆坦索洛新浓度
Figure imgf000010_0001
表二、 由实施例 1所获取的坦索洛新緩释剂型， 投药给六个成年男 性在空腹状态下， 其平均血浆坦索洛新浓度
Figure imgf000011_0001
实施例 2: 坦索洛新緩释剂型的配方与制法 (二）
坦索洛新盐酸盐 1.60克重
异丁烯酸聚合物 160克重
微结晶纤维素 360.0克重
柠檬酸三乙酯 35，6克重
二十二酸甘油酯 210.38克重
乙基纤维素 148.0克重
膜衣
异丁烯酸聚合物 57.12克重
1N NH3 19.29克重
滑石粉 8.52克重
柠檬酸三乙酯 28.58克重
调配：
1.将坦索洛新、 异丁烯酸聚合物、 微结晶纤维素及二十二酸甘油酯加 以混合以获取混合物。
2.将乙基纤维素及柠檬酸三乙酯湿式混合， 而后加入前述混合物中， 并以桥压造粒机、 离心搓圆机进行造粒。
3. 将圆粒干燥。
4.将包含异丁烯酸聚合物、 滑石粉及杵檬酸三乙酯的膜衣预混物混合 均匀。
5.将干燥的圆粒放入流动层造粒机， 并将膜衣预混物溶解于适当溶剂 后， 喷洒于圆粒表面。 .
请参阅图 及表三与表四所示， 将实施例 2所获取的圆粒填充于胶嚢 内， 而后以交叉试验方式 (cross over method), 给予六个成年男性分别在饱 食及空腹状态下投药。 在适当时间间隔后， 抽取受试者血液并利用可信的 分析方法测量血浆中坦索洛新的浓度。 数据显示本发明所揭露的坦索洛新 緩释剂型十分稳定。
表三、 由实施例 2所获取的坦索洛新緩释剂型， 投药给六个成年男性 在饱食状态下， 其平均血浆坦索洛新浓度
Figure imgf000012_0001
表四、 由实施例 2所获取的坦索洛新緩释剂型， 投药给六个成年男性 在空腹状态下， 其平均血浆坦索洛新浓度
Figure imgf000013_0001
实施例 3: 与传统坦索洛新緩释剂型的胶嚢进行释放速率试验
请参阅图 3及表五与表六所示， 将传统坦索洛新緩释剂型胶嚢 (商品名 为 Flomax (Boehringer Ingelheim)), 以交叉试驗方式 (cross over method), 给 予六个成年男性分别在饱食及空腹状态下投药。 在适当时间间隔后， 抽取 受试者血液并利用可信的分析方法测量血浆中坦索洛新的浓度。 数据显示 在饱食状态及空腹状态， 传统的坦索洛新緩释剂型具有两种不同的曲线下 面积。 因此， 传统的坦索洛新緩释剂型其緩释效果是不稳定的。
表五、 传统坦索洛新緩释剂型， 投药给十二个成年男性在饱食状态 下， 其平均血浆坦索洛新浓度 时间 （hr) 饱食状态下血浆中的坦索洛新浓 度 (ng/ml)
0 0
1 0.01
2 0.51
3 1.97 4 3.57
5 5.63
5.5 6.39
6 6.24 .
6.33 6.62
6.67 6.98
7 6.39
7.33 7.48
7.67 6.20
8 6.15
12 5.07 表六、 传统坦索洛新缓释剂型， 投药给十二个成年男性在空腹状
, 其平均血浆坦索洛新浓度
Figure imgf000014_0001
根据图 1至图 3所示， 明显可知在饱食状态下并不影响由本发明实施 例 1及实施例 2所获取的坦索洛新緩释剂型的药物动力学。 然而， 传统的 坦索洛新緩释剂型在饱食状态下， 其血浆中的坦索洛新浓度则严重受到食 物的影响。 因此， 根据上述的实施例所示， 本发明的坦索洛新緩释剂型具有下列 明显的优点：
1.在本发明所揭露的制造过程中， 使用圆粒形成剂作为润滑剂， 令人 惊异地发现可解决在制造过程中使用丙烯酸聚合物或丙烯酸共聚物在高温 下所导致的胶状问题。
2. 本发明所揭露的坦索洛新緩释剂型， 令人惊异地展现了不受食物影 响的结果。 因此， 可以在病人饭前或饭后安全的给予药物， 而不受食物限 制。
根据本发明可作的不同修正及变化对于熟悉本领域的技术人员而言均 显然不会偏离本发明的范围与精神。 虽然本发明已叙述特定的优选具体事 上， 在实施本发明的已述模式方面， 对于熟悉本领域的技术人员而言显而 易知的不同修正也被涵盖于本发明的保护范围内。

Claims

权利要求书
1. 一种含有坦索洛新的緩释剂型， 其包括有效量的坦索洛新或其医 药上可接受的盐类、 10%-50%(w/w)纤维素类疏水性高分子化合物作为释放 速率调控剂及 10%-30%(w/w)圆粒形成剂与 30%-50%(w/w)稀释剂， 其中， 各组分之和为 100% , 且该緩释剂型可在体外溶离试验最初的二小时内释 放 少于 5%的坦索洛新或其医药上可接受的盐类。
2. 如权利要求 1 所述的緩释剂型， 其中所述稀释剂为乳糖、 淀粉、 甘露醇、 羧甲基纤维素钠、 淀粉钠、 微结晶纤维素、 滑石粉、 硬酯酸、 硬 酯酸盐、 延胡索硬酯酸钠、 二十二酸甘油酯或其组合。
3. 如权利要求 1 或 2所述的緩幹剂型， 其中所述纤维素类疏水性高 分子化合物为酸碱相关性的纤维素或非酸碱相关性的纤维素。
4. 如权利要求 3 所述的緩释剂型， 其中所迷纤维素类疏水性高分子 化合物为异丁烯酸聚合物、 羧甲基纤维素钠、 醋酸纤维素、 乙基纤维素、 羧丙基甲基纤维苯二甲酸盐、 羟丙甲基纤维素醋酸琥珀酸酯、 聚醋酸乙烯 磷酸盐、 乙酸苯二微结晶纤维素或其组合。
5. 如权利要求 1 所述的緩释剂型， 其中所述圆粒形成剂为甘油酯类 或蜡质物质。
6. 如权利要求 5 所述的緩释剂型， 其中所迷圆粒形成剂为甘油三醋 酸酯、 甘油硬脂酸酯、 二十二酸甘油酯、 石蜡、 棕榈蜡或其组合。
7. 如权利要求 1 所述的緩释剂型， 其中所迷坦索洛新的含量占緩释 剂型的 0.01-3%(w/w：)。
8. 如权利要求 Ί 所述的緩释剂型， 其中所迷坦索洛新的含量占緩释' 剂型的 0,03-3%(w/w；)。
9. 一种含有坦索洛新的緩释剂型的制造方法， 包括将有效量的水溶 性坦索洛新或其医药上可接受的盐类、 圆粒形成剂、 幹放速率调控剂及稀 释剂加以混合以形成混合物； 预备一膜衣预混物； 将混合物制成颗粒， 将 膜衣预混物包覆于颗粒上。
10. 如权利要求 9所述的制造方法， 其中膜衣预混物是溶解于水或有 机溶剂。
1.1. 如权利要求 9所述的制造方法， 其中释放速率调控剂为纤维素类 疏水性高分子化合物。
12. 如权利要求 11 所述的制造方法， 其中所述疏水性高分子化合物 为异丁烯酸聚合物、 羧甲基纤维素钠、 醋酸纤维素、 乙基纤维素、 羧丙基 甲基纤维苯二曱酸盐、 羟丙甲基纤维素醋酸琥珀酸酯、 聚醋酸乙烯磷酸 盐、 乙酸苯二微结晶纤维素或其组合。
13. 如权利要求 9所述的制造方法， 其中所述圆粒形成剂为甘油三醋 酸酯、 甘油硬脂酸酯、 二十二酸甘油酯、 石蜡、 棕榈蜡或其组合。
14. 如权利要求 9所述的制造方法， 其中所述膜衣预混物是由一种或 多种乙基纤维素、 柠檬酸三乙酯、 异丁烯酸聚合物、 滑石粉或其组合所组 成。
PCT/CN2007/000200 2007-01-18 2007-01-18 Preparation de tamsulosine a liberation prolongee et procede de production associe WO2008089593A1 (fr)

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US8532306B2 (en) 2007-09-06 2013-09-10 Lg Electronics Inc. Method and an apparatus of decoding an audio signal

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US20050186275A1 (en) * 2004-02-23 2005-08-25 Standard Chem. & Pharm. Co. Ltd. Sustained release tamsulosin formulations
CN1744889A (zh) * 2002-12-20 2006-03-08 兰贝克赛实验室有限公司 坦洛新的控释药物组合物

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CN1744889A (zh) * 2002-12-20 2006-03-08 兰贝克赛实验室有限公司 坦洛新的控释药物组合物
US20050186275A1 (en) * 2004-02-23 2005-08-25 Standard Chem. & Pharm. Co. Ltd. Sustained release tamsulosin formulations

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8532306B2 (en) 2007-09-06 2013-09-10 Lg Electronics Inc. Method and an apparatus of decoding an audio signal

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