CN1067915C - 细颗粒染料或药物制剂的生产 - Google Patents
细颗粒染料或药物制剂的生产 Download PDFInfo
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- CN1067915C CN1067915C CN94113697A CN94113697A CN1067915C CN 1067915 C CN1067915 C CN 1067915C CN 94113697 A CN94113697 A CN 94113697A CN 94113697 A CN94113697 A CN 94113697A CN 1067915 C CN1067915 C CN 1067915C
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
- C09B67/0071—Process features in the making of dyestuff preparations; Dehydrating agents; Dispersing agents; Dustfree compositions
- C09B67/0092—Dyes in solid form
- C09B67/0095—Process features in the making of granulates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
通过使相对粗颗粒分散相或溶液转化成水中的胶体分散相生产细颗粒、基本上非晶的染料或药物制剂的方法，其中通过在染料或药物熔点之上的温度下混入适当的热水(适当时在压力下)或水保护胶体溶液制备胶体分散相，以致得到熔在水介质中的乳液，再直接喷雾干燥或通过冷却转化成悬浮液。
Description
本发明涉及一种改进的在水中溶解度低的化合物微粉化的方法。
因要求提高溶解度低的药物的生物利用率，或溶解度低的染料的着色强度，出现了各种生产小颗粒的在水中溶解度低的化合物的方法。例如EP65193。EP169618和US5133908描述的方法，将药物或染料变成与水可混溶的溶剂的分子溶液，然后通过将溶液加入水中或反之使药物或染料以细颗粒形式再度沉淀。然而，这些方法存在缺陷，即必需用相对大量的溶剂溶解药物或染料(通常其在有机溶剂中的溶解度也低)以制成细颗粒剂型。
本发明的目的是在仍获得药物和染料的极细颗粒剂型的同时使所用溶剂的量最小。
溶剂量的减少是以本发明的方法取得的，因为不必制备药物或染料在与水可混溶的溶剂中的中间分子溶液，相反本发明的方法使分散在水或有机相中的药物或染料在剧烈湍动下瞬时暴露于其熔点之上的温度下，然后通过快速冷却至熔点以下，使得到的细颗粒乳液转变成固体在水中的稳定分散相。随后可用传统方法使该分散相浓缩和干燥，或者可不经过前面的冷却，立即将乳液喷雾干燥。两种情况的产物均是粉剂，当其再分散于水中时得到染料或药物的细颗粒分散相。
配制过程中对溶剂的需要的取消或减少不仅具有降低成本的优点，而且第一次使生产稳定的毫微颗粒如苯酰降脂丙酰成为可能，因为当固体颗粒由水分散相生产时，它们通过奥氏熟化(ostwaldtripening)直接长成较大的颗粒，而使微粉化的结果无效。作为本方法中间产物的迅速生产的乳液中设有观测到奥氏熟化。而通过完全或基本上取消溶剂(或残余物在分散介质中溶解度方面导致的降低)，又使奥氏熟化减慢到这样的程度：以致在直接喷雾干燥的过程中观察不到颗粒增长。
然而，有些物质不适合于完全不用溶剂加工，因为它们的水分散相结块而不能计量。苯酰降脂丙酰就是这样的一个例子。因此，根据本发明，这种类型的物质不分散于水中，而是溶解(如果它们易溶于适当的溶剂)或分散于少量的有机溶剂中。完全溶解是不必要的；只要悬浮液可以计量就足够了。然后，在剧烈湍动下和适当时在压力下，将颗粒物质熔点之上温度下的水或水保护的胶体溶液加入该溶液或悬浮液中，方法的剩余部分如前所述，即熔融乳液直接喷雾干燥，或者使得到的细颗粒乳液迅速冷却，和适当时使得到的悬浮液脱水和干燥。迅速冷却可通过加冷水方便地达到。
将水或水保护的胶体溶液加入染料或药物的悬浮液或溶液中时，产生湍动的方法并不重要。例如，剧烈搅拌或振动均可。最简单的，并因此优选的，是以压缩流体喷射一种或更好为两种组分，以便直接紧密混合而不用机械手段。
“细颗粒”或“胶态分散”意指颗粒尺寸低于1.5μm，优选低于1μm。
“基本上非晶形的”意指本发明生产的产品多于一半、优选多于70％，特别地近似100％为X射线非晶形的。
本发明对于药物比对染料还要重要，因为对于染料，本发明“仅”有优点，即由于分散较好，所以用较少染料可取得相同的着色效果，而对药物这种特殊的物质，本发明是当溶解度低或为零时在吸收性方面的改进，其对于效果是至关重要的。
适合于混合的温度范围是从40至250℃，优选60至200℃。
保护肢体用于稳定初始形成的乳液和其经冷却产生的分散相。此外，它们保证根据本发明适合生产的粉剂容易再分散。保护胶体的例子是各种来源的凝胶、酪蛋白、阿拉伯树胶、lysalbinic酸、淀粉、糊精、果胶、甲基纤维素、羧甲基纤维素、羟丙基纤维素、藻酸盐、聚乙烯醇、聚乙烯吡咯烷酮和聚丙烯酸酯类。
“相对粗颗粒”意指相对于最终产品为粗颗粒。该颗粒尺寸实际上不重要，可在约1至2000μm的范围内。
适合的溶剂原则上是在水中溶解至少10％的所有溶剂。它们还必须是可蒸馏而不分解的。可涉及的例子是：醇类、醚类、酮类、酯类、缩醛类、二甲基甲酰胺、N-甲基吡咯烷酮和二甲亚砜。
为提高终产品的机械稳定性，方便的方法是向胶体中加入增塑剂或填料如糖或糖醇类，例如蔗糖、葡糖、乳糖、转化糖、山梨醇、甘露糖醇或甘油。
当终产品为干粉形时，它包含0.5至20％(wt)，优选约10％(wt)的低溶解度染料或药物，10至50％(wt)保护性肢体和30至80％(wt)增塑剂和适当时的少量其它辅助剂如乳化剂、抗氧化剂和其它稳定剂。
当使用有机溶剂时，可根据其沸点用传统方法去除，例如通过蒸馏，适当时在减压下蒸馏，或用与水不混溶的溶剂萃取。在后一种情况中，在不需去除水、直接作溶剂情况下用使用异丙醇时得到的共沸物，已被证明是可行且方便的。但溶剂的去除优选通过喷雾干燥或喷雾造粒与水的去除一起发生。
使用水溶性保护胶体时，得到的干粉可再溶于水中得到颗粒尺寸＜1μm范围内的药物的均匀细分散相。得到的药物水溶胶，尽管是细分散相，光化学稳定性试验证明是极稳定的。
适合的染料和药物的例子是类胡萝卜素、戊脉安、anipamil、苯丙酰苯心安和安克痉(biperidene)。
实施例中所列的份数是按重量计的。
实施例1
β--胡萝卜素的无溶剂微粉化
染料分散相：
使用电磁搅拌器使21份β--胡萝卜素和2.3份抗坏血酸棕榈酸酯分散在240份水中。
保护胶体溶液：
将57.9份B型凝胶(100Bloom)和97.5份乳糖溶解于70℃的4000份水中。将得到的溶液冷却至25℃。
微粉化的生产示于图1中。染料分散相(1)通过泵(3)以230份/小时的速度泵入第一混合室(6)，在此与4740份水流混合，该水流事先已由恒温器(5)加热至227℃并由泵(4)每小时从容器(2)泵入。与热水混合导致混合物猝然达到217℃，其高于β--胡萝卜素的熔点(184℃)。在217℃下0.5s之后，使得到的β--胡萝卜素乳液在第二混合室(7)与保护肢体溶液(8)混合，其由泵(9)以32,200份/小时的流速泵入。得到的细颗粒微粉通过限压阀(10)放出。此方法生产的β--胡萝卜素颗粒平均尺寸为576nm(由光子校正光谱测定)，为胶态稳定分散形式。
实施例2
由固含量30%的乳液生产苯酰降脂丙酰的微粉
药物溶液：
将500份苯酰降脂丙酰溶于50℃的1500份异丙醇中。
保护胶体溶液：
将125g抗坏血酸棕榈酸酯在搅拌下溶于10,000份70℃PH9(加1M氢氧化钠溶液)的水中。在搅拌下向得到的溶液中溶入2000份B型凝胶(30Bloom)和2875份乳糖。
微粉化：
微粉的生产如图2所示。药物溶液(1)开始在50℃，保护胶体溶液(2)开始为80℃。药物溶液由泵(3)以2000份/小时的流速通过120℃油浴中的热交换器(5)泵入混合室(7)。保护胶体溶液(2)由泵(4)以9000份/小时的流速通过130℃的热交换器(6)进入，药物溶液在混合室与肢体溶液混合。混合物的温度达到92℃，其高于苯酰降脂丙酰的熔点(80℃)。得到的乳液通过限压阀(8)放出，经过热管(9)直接送入喷雾塔(10)，并在此用入口温度160℃出口温度80℃的空气干燥。从而得到自由流动的粉剂(11)，其再分散于水中时得到苯酰降脂丙酰的胶态分散相，苯酰降脂丙酰的颗粒尺寸为0.66μm(体积平均，由激光衍射测定)。
实施例3
levemopamil hydrochloride微粉的生产
药物分散相：
将9g levemopamil.HCl与1.8g抗坏血酸棕榈酸酯分散于31.7g异丙醇和4.3g水的混合物中。
保护胶体溶液：
用NaOH使15gB型凝胶(100Bloom)和22.5g乳糖在1升水中的溶液调至PH为11.4。
微粉化：
微粉的生产如图1所示。药物分散相(1)由泵(3)以0.55kg/h的速度泵入第一混合室(6)，在此与由泵(4)从容器(2)泵入且已经恒温器(5)加热至210℃的1kg/h水流混合。与热水混合导致温度升至185℃，其高于levemopamil.HCl的熔点(182℃)。在185℃少于0.5s后，使得到的levemopamil.HCl乳液在第二混合室(7)与由泵(9)以9kg/h的流速泵入的保护肢体溶液(8)混合。得到的微粉通过限压阀(10)放出。将该微粉喷雾干燥得到药物含量为22.3％的粉剂。该粉剂再溶于水中得到平均尺寸为580nm(由动态光散射测定)的levemopamil.HCl毫微颗粒。
实施例4
苯丙酰苯心安．HCl微粉的生产
药物分散相：
如实施例3，但用苯丙酰苯心安．HCl替代levemopamil.HCl。
保护胶体溶液：
如实施例3，但PH11.0。
微粉的生产：
如实施例3生产微粉。混合室(6)的温度为177℃，从而高于苯丙酰苯心安，HCl的熔点(174℃)。喷雾干燥得到药物含量为23.3％的粉剂，再溶于水中之后毫微颗粒的尺寸为350nm(动态光散射)。
实施例5
anipamil.HCl毫微颗粒分散相的生产
药物分散相的生产：
将21g anipamil.HCl与0.24g10×乙氧基化异壬基酚分散于240g水。
保护胶体溶液的制备：
用NaOH使15g/lB型凝胶(100Bloom)的溶液调至PH9。
微粉化：
微粉化如实施例4，变化如下：分散相泵入速度： 2kg/h水泵入速度： 4kg/h保护胶体溶液泵入速度： 30kg/h热交换器温度： 100℃第一混合室(6)温度： 93℃anipamil.HCl的熔点： 63℃
得到的水分散相中anipamil.HCl毫微颗粒的平均尺寸为220nm(动态光散射)。此毫微颗粒分散相中药物含量为0.45％。
实施例6
鸡油菌黄质的微粉化
药物分散液的制备：
将21g鸡油菌黄质和4.6g抗坏血酸棕榈酸酯分散于223g水和12g 1M NaOH的混合物中。
保护胶体溶液的制备如实施例5。
微粉化如实施例4，变化如下：分散相泵入速度： 1.1kg/h水泵入速度： 6kg/h保护胶体溶液泵入速度： 30kg/h热交换器温度： 240℃第一混合室(6)温度： 223℃鸡油菌黄质的熔点： 211℃
得到的水分散相中鸡油菌黄质毫微颗粒的平均尺寸为370nm(动态光散射)。毫微颗粒分散相中药物含量为0.21％。
实施例7
nesapidil微粉的生产
药物分散相的制备：
将3g nesapidil和0.6g抗坏血酸棕榈酸酯分散于31.7g异丙醇和4.3g水的混合物中。
保护胶体溶液的制备如实施例5。
微粉化：
微粉化如实施例4，变化如下：热交换器温度： 210℃第一混合室(6)温度： 175℃nesapidil熔点： 164℃
喷雾干燥得到nesapidil含量为10.3％的粉剂。再溶于水中后平均颗粒尺寸为350nm(动态光散射)。
Claims (5)
1．一种通过使在水中溶解至少10％的有机溶剂中的染料或药物的相对粗颗粒分散相或有机溶液转化成水中的胶体分散相生产细颗粒、基本上非晶的染料或药物制剂的方法，特征在于使染料或药物的水分散相或有机溶剂在染料或药物的熔点之上的温度下，适当时在压力下，与水或含水保护胶体溶液湍动混合，得到的熔融乳液直接喷雾干燥或通过冷却转化成悬浮液。
2．如权利要求1所述的方法，其中没有使用有机溶剂。
3．如权利要求1或2所述的方法，其中热的熔融乳液形成后，尽可能快地冷却。
4．如权利要求1或2所述的方法，其中通过传统方法从得到的悬浮液中去除水或水/溶剂混合物以提供易再分散的粉剂。
5．如权利要求3所述的方法，其中通过传统方法从得到的悬浮液中去除水或水/溶剂混合物以提供易再分散的粉剂。
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| US4144025A (en) * | 1977-05-02 | 1979-03-13 | Polaroid Corporation | Process for making dispersions comprising spherical particles |
| DE3119383A1 (de) * | 1981-05-15 | 1982-12-02 | Basf Ag, 6700 Ludwigshafen | Verfahren zur herstellung von feinverteilten, pulverfoermigen carotinodpraeparaten |
| CH658066A5 (de) * | 1984-03-15 | 1986-10-15 | Ciba Geigy Ag | Verfahren zur herstellung von granulaten wasserloeslicher farbstoffe. |
| CA1282405C (en) * | 1984-05-21 | 1991-04-02 | Michael R. Violante | Method for making uniformly sized particles from water-insoluble organic compounds |
| FR2608988B1 (fr) * | 1986-12-31 | 1991-01-11 | Centre Nat Rech Scient | Procede de preparation de systemes colloidaux dispersibles d'une substance, sous forme de nanoparticules |
| FR2634397B2 (fr) * | 1986-12-31 | 1991-04-19 | Centre Nat Rech Scient | Procede de preparation de systemes colloidaux dispersibles d'une proteine sous forme de nanoparticules |
| EP0572494B1 (en) * | 1991-02-18 | 1999-08-25 | Commonwealth Scientific And Industrial Research Organisation | Composition for use in transdermal administration |
| AU1229892A (en) * | 1992-02-11 | 1993-09-03 | Glaxo Group Limited | Benzenedimethanol derivative suitable for micronisation |
-
1993
- 1993-09-01 DE DE4329446A patent/DE4329446A1/de not_active Withdrawn
-
1994
- 1994-08-23 IL IL11075994A patent/IL110759A0/xx not_active IP Right Cessation
- 1994-08-25 AT AT94113270T patent/ATE174529T1/de not_active IP Right Cessation
- 1994-08-25 ES ES94113270T patent/ES2125384T3/es not_active Expired - Lifetime
- 1994-08-25 DK DK94113270T patent/DK0641596T3/da active
- 1994-08-25 DE DE59407483T patent/DE59407483D1/de not_active Expired - Lifetime
- 1994-08-25 CA CA002130857A patent/CA2130857A1/en not_active Abandoned
- 1994-08-25 EP EP94113270A patent/EP0641596B1/de not_active Expired - Lifetime
- 1994-08-30 AU AU71582/94A patent/AU678840B2/en not_active Ceased
- 1994-08-31 JP JP20723994A patent/JP3773275B2/ja not_active Expired - Lifetime
- 1994-08-31 MX MX9406643A patent/MX195052B/es not_active IP Right Cessation
- 1994-09-01 CN CN94113697A patent/CN1067915C/zh not_active Expired - Lifetime
-
1995
- 1995-12-18 US US08/573,876 patent/US5700471A/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4540602A (en) * | 1979-04-13 | 1985-09-10 | Freund Industry Company, Limited | Process for the preparation of activated pharmaceutical compositions |
| US4844934A (en) * | 1986-03-26 | 1989-07-04 | Basf Aktiengesellschaft | Preparation of finely divided, water-dispersable carotenoid formulations |
| EP0278284A1 (de) * | 1987-01-24 | 1988-08-17 | BASF Aktiengesellschaft | Pulverförmige, wasserdispergierbare Carotinoid-Zubereitungen und Verfahren zu ihrer Herstellung |
| EP0410236A2 (de) * | 1989-07-25 | 1991-01-30 | F. Hoffmann-La Roche Ag | Verfahren zur Herstellung von Carotinoidpräparaten |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07163862A (ja) | 1995-06-27 |
| MX195052B (en) | 2000-01-21 |
| DK0641596T3 (da) | 1999-08-23 |
| US5700471A (en) | 1997-12-23 |
| AU678840B2 (en) | 1997-06-12 |
| CA2130857A1 (en) | 1995-03-02 |
| ES2125384T3 (es) | 1999-03-01 |
| JP3773275B2 (ja) | 2006-05-10 |
| EP0641596B1 (de) | 1998-12-16 |
| EP0641596A3 (de) | 1995-11-15 |
| AU7158294A (en) | 1995-03-16 |
| DE59407483D1 (de) | 1999-01-28 |
| DE4329446A1 (de) | 1995-03-02 |
| EP0641596A2 (de) | 1995-03-08 |
| CN1105902A (zh) | 1995-08-02 |
| ATE174529T1 (de) | 1999-01-15 |
| IL110759A0 (en) | 1994-11-11 |
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