JP4370429B2 - Process for producing sustained release microspheres - Google Patents
Process for producing sustained release microspheres Download PDFInfo
- Publication number
- JP4370429B2 JP4370429B2 JP27664798A JP27664798A JP4370429B2 JP 4370429 B2 JP4370429 B2 JP 4370429B2 JP 27664798 A JP27664798 A JP 27664798A JP 27664798 A JP27664798 A JP 27664798A JP 4370429 B2 JP4370429 B2 JP 4370429B2
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- JP
- Japan
- Prior art keywords
- weight
- microspheres
- drug
- release microspheres
- producing sustained
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- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
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- Medicinal Preparation (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Description
【0001】
【本発明の背景】
本発明は、徐放性マイクロスフエアの製造法に関する。特に、常温で固体の油脂系マトリックスに薬物を分散したこのタイプの徐放性製剤の製造法に関する。
【0002】
マイクロスフエアは、ドライシロップ及び懸濁液剤として好適に用いられる。マイクロスフエアは、服用量の調節が容易なこと、および高齢者および小児に対しても投与が容易なこと等の理由で錠剤やカプセル剤に見られない特徴を持っている。徐放性マイクロスフエアの一つのタイプとして、例えば特開昭61−109711に開示されているように、セルロース系またはアクリル系ポリマーをマトリックスとして使用した製剤や、特開平2−223533および特開平2−275817にそれぞれ開示されているポリグリセリン脂肪酸エステルおよび硬化綿実油に代表される油脂系マトリックスを使用する製剤が知られている。
【0003】
油脂系マトリックスを使用するマイクロスフエアは、溶融したマトリックスに薬物の粒子を分散し、遠心噴霧によって微細な液滴をつくり、冷却することによって溶融マトリックス/薬物分散液から直接製造することができる利益を有する。
【0004】
ところが公知の油脂系マイクロスフエアは、経口投与する時ロウや脂肪の塊を服用したような服用感を与えるほか、遠心噴霧の作業性(微小液滴の形成し易さ)も満足ではない。
【0005】
本発明はこのため、油脂系マトリックス基剤の改良により、これらの欠点を改良する。
【0006】
【本発明の開示】
本発明においては、硬化油脂5〜50重量%、ステアリルアルコール10〜30重量%、ショ糖高級脂肪酸エステル5〜30重量%を含んでいるワックス状混合物を使用する。このワックス状混合物は常温では固体であるが、これを溶融して液化し、その中へ薬物を分散し、分散液を常法により遠心噴霧冷却(遠心スプレーチリング)する。この操作によって徐放性のマイクロスフェアが得られる。
【0009】
一般に徐放性製剤に使用される薬物が本発明においても使用し得る。その非限定的な例は、テオフィリン、イブプロフェン、デキストロメトルファン、ニコランジル、プロプラノロール、ケトチフエン、ジルチアゼム、メチルドパ、シメチジン、イブジラスト、ピロキシカム、ジアゼパム、ジクロフエナック、インドメタシン、スリンダク、ニフェジピン、ロラゼパム、グリペンクラミド、スピロノラクトン、フアモチジンを含む。
【0010】
マイクロスフエアは少割合の他の慣用の添加剤を含むことができる。その例はカルナウバロウ、木ロウ、鯨ロウ、ミツロウなどのロウ類、ステアリン酸またはパルミチン酸のような高級脂肪酸、パラフィン、マイクロクリスタリンワックス、ワセリンなどの炭化水素類、マクロゴール6000のような固体PEG、無機充填剤例えばタルク、ステアリン酸マグネシウムなど、糖類例えばマンニット、シュークロースなど、その他の添加剤としてシリコーン油などである。マイクロスフエアの強度を増加させるため、あるいは放出制御のために、水不溶性高分子(例エチルセルロース等)をワックス融解液に溶解して用いてもよい。
【0011】
遠心噴霧法によるマイクロスフエアのつくり方は公知である。例えばここに記載したワックス状混合物を加熱溶融し、これへ薬物の微粉末を添加して均一に分散する。この分散液を回転円板の中心へ供給し、薄い層状に飛ばして噴霧し、生成した微小液滴を冷却固化して集め、必要により篩分する。得られる球形マイクロスフエア粒子の粒子径は一般に回転円板の周速度および溶融分散液の供給速度の関数である。一つの目安として、25,000rpmで回転している直径65mmの回転円板の中心へ130〜140g/minの割合で分散液を供給する時、粒子径50〜100μmのマイクロスフエアが得られる。冷却は室温の空気によって行うことができる。
【0012】
実施例1
ショ糖ステアリン酸エステル(リョート−シュガーエステルS370、HLB=3)600g,ステアリルアルコール600g,硬化ヒマシ油450gを90℃に加熱溶融し、これへテオフィリン1100gを投入して10分間攪拌して分散させた。これを90℃に保温しながら25,000rpmで回転している直径65mmのステンレス製ディスクの中心へ133g/minの割合で滴下し、室温雰囲気で冷却し、粒子径50〜100μmのマイクロスフエアを得た。
【0013】
実施例2
実施例1で使用した同じショ糖ステアリン酸エステル450g,硬化ヒマシ油1000g,ステアリルアルコール350g,タルク250gを90℃に加熱溶融し、これへテオフィリン900gを投入して10分間攪拌して分散させた。これを実施例1と同じ条件で遠心噴霧し、冷却して粒子径50〜100μmのマイクロスフエアを得た。
【0014】
溶出試験
テオフィリン100mgに相当する実施例1および2のマイクロスフエアを取り、日局溶出試験法(試験液JP II液、パドル回転数50rpm)に従ってテオフィリン溶出パターンを試験し、以下の結果を得た。
【0015】
【0016】
上の結果から、本発明によるマイクロスフエアは8〜12時間にわたって持続的にテオフィリンを比較的コンスタントに放出することがわかる。[0001]
[Background of the present invention]
The present invention relates to a method for producing sustained-release microspheres. In particular, the present invention relates to a method for producing this type of sustained-release preparation in which a drug is dispersed in a solid oil-based matrix at room temperature.
[0002]
Microspheres are preferably used as dry syrups and suspensions. Microspheres have characteristics that are not found in tablets and capsules because of easy adjustment of dosage and ease of administration to the elderly and children. As one type of sustained-release microsphere, for example, as disclosed in JP-A-61-109711, a preparation using a cellulose or acrylic polymer as a matrix, JP-A-2-223533, and JP-A-2 Formulations using an oil-based matrix typified by polyglycerol fatty acid esters and hydrogenated cottonseed oil, each disclosed in US Pat.
[0003]
Microspheres using an oleaginous matrix benefit that can be produced directly from a molten matrix / drug dispersion by dispersing drug particles in a molten matrix, creating fine droplets by centrifugal spraying and cooling Have
[0004]
However, known oil-based microspheres give a feeling of taking a wax or fat mass when administered orally, and are not satisfactory in the workability of centrifugal spraying (easy to form microdroplets).
[0005]
The present invention thus ameliorates these drawbacks by improving the oil based matrix base.
[0006]
[Disclosure of the present invention]
In the present invention, a waxy mixture containing 5 to 50% by weight of hardened fats and oils, 10 to 30% by weight of stearyl alcohol, and 5 to 30% by weight of higher fatty acid esters of sucrose is used. This wax-like mixture is solid at room temperature, but is melted and liquefied, the drug is dispersed therein, and the dispersion is subjected to centrifugal spray cooling (centrifugal spray chilling) by a conventional method. By this operation, sustained-release microspheres can be obtained.
[0009]
Drugs generally used in sustained release formulations can also be used in the present invention. Non-limiting examples include theophylline, ibuprofen, dextromethorphan, nicorandil, propranolol, ketotifen, diltiazem, methyldopa, cimetidine, ibudilast, piroxicam, diazepam, diclofenac, indomethacin, sulindac, nifedipine, lolazepam, pendant Contains huamotidine.
[0010]
The microsphere can contain a small proportion of other conventional additives. Examples include waxes such as carnauba wax, tree wax, whale wax, beeswax, higher fatty acids such as stearic acid or palmitic acid, hydrocarbons such as paraffin, microcrystalline wax, petrolatum, solid PEG such as macrogol 6000, Inorganic fillers such as talc and magnesium stearate, sugars such as mannitol and sucrose, and other additives such as silicone oil. In order to increase the strength of the microsphere or to control the release, a water-insoluble polymer (eg ethyl cellulose) may be dissolved in a wax melt and used.
[0011]
A method for producing microspheres by centrifugal spraying is known. For example, the wax-like mixture described here is melted by heating, and a fine powder of drug is added thereto to uniformly disperse. This dispersion is supplied to the center of the rotating disk, sprayed in a thin layer, and the generated fine droplets are cooled and solidified, and are sieved as necessary. The particle size of the resulting spherical microsphere particles is generally a function of the peripheral speed of the rotating disk and the feed rate of the molten dispersion. As one guideline, when a dispersion is supplied at a rate of 130 to 140 g / min to the center of a rotating disc having a diameter of 65 mm rotating at 25,000 rpm, a microsphere having a particle size of 50 to 100 μm is obtained. Cooling can be done with room temperature air.
[0012]
Example 1
600 g of sucrose stearate (Ryoto-sugar ester S370, HLB = 3), 600 g of stearyl alcohol and 450 g of hardened castor oil were heated and melted at 90 ° C., and 1100 g of theophylline was added thereto and stirred for 10 minutes to disperse. . This was dropped at a rate of 133 g / min onto the center of a 65 mm diameter stainless steel disc rotating at 25,000 rpm while keeping it at 90 ° C., cooled in a room temperature atmosphere, and microspheres with a particle size of 50 to 100 μm were added. Obtained.
[0013]
Example 2
450 g of the same sucrose stearate used in Example 1, 1000 g of hardened castor oil, 350 g of stearyl alcohol, and 250 g of talc were heated and melted at 90 ° C., 900 g of theophylline was added thereto and stirred for 10 minutes to disperse. This was subjected to centrifugal spraying under the same conditions as in Example 1 and cooled to obtain microspheres having a particle size of 50 to 100 μm.
[0014]
Dissolution test The microspheres of Examples 1 and 2 corresponding to 100 mg of theophylline were taken, and the theophylline dissolution pattern was tested according to the Japanese dissolution test method (test solution JP II solution, paddle rotation speed 50 rpm). The result was obtained.
[0015]
[0016]
From the above results, it can be seen that the microspheres according to the present invention release theophylline relatively constantly over a period of 8-12 hours.
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP27664798A JP4370429B2 (en) | 1998-09-10 | 1998-09-10 | Process for producing sustained release microspheres |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP27664798A JP4370429B2 (en) | 1998-09-10 | 1998-09-10 | Process for producing sustained release microspheres |
Publications (2)
Publication Number | Publication Date |
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JP2000086502A JP2000086502A (en) | 2000-03-28 |
JP4370429B2 true JP4370429B2 (en) | 2009-11-25 |
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Application Number | Title | Priority Date | Filing Date |
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JP27664798A Expired - Lifetime JP4370429B2 (en) | 1998-09-10 | 1998-09-10 | Process for producing sustained release microspheres |
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Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE60021570T2 (en) | 1999-06-07 | 2006-05-24 | Altana Pharma Ag | NEW PREPARATION AND PHARMACEUTICAL FORM CONTAINS AN ACID ELASTILE PROTON PUMP INHIBITOR |
CA2407154A1 (en) | 2000-04-27 | 2001-11-01 | Verion, Inc | Zero order release and temperature-controlled microcapsules and process for the preparation thereof |
UA80393C2 (en) | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
DE10061137B4 (en) * | 2000-12-07 | 2016-10-06 | Takeda Gmbh | New pharmaceutical preparation |
JP5054062B2 (en) * | 2009-05-07 | 2012-10-24 | 株式会社カネカ | Method for producing microcapsules using solid fat |
WO2012126813A1 (en) | 2011-03-21 | 2012-09-27 | Boehringer Ingelheim International Gmbh | Solid ambroxol-containing preparation |
WO2020051585A1 (en) * | 2018-09-07 | 2020-03-12 | R.P. Scherer Technologies, Llc | Solid or semisolid lipid based dosage form stabilization through curing and addition of low hlb surfactant(s) |
-
1998
- 1998-09-10 JP JP27664798A patent/JP4370429B2/en not_active Expired - Lifetime
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