JP4370429B2 - Process for producing sustained release microspheres - Google Patents

Description

【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)

The drug is dispersed in a melt of a solid wax-like mixture at room temperature containing 5 to 50% by weight of hardened fat and oil, 10 to 30% by weight of stearyl alcohol, and 5 to 30% by weight of sucrose higher fatty acid ester. A process for producing sustained-release microspheres characterized by spraying by a centrifugal spraying method and cooling.   The drug is selected from theophylline, ibuprofen, dextromethorphan, nicorandil, propranolol, ketotifen, diltiazem, methyldopa, cimetidine, ibudilast, piroxicam, diazepam, diclofenac, indomethacin, sulindac, nifedipine, lorazepam, glypenclamide, sp The method of claim 1.