JPH11335300A - Sustained release preparation using glycerol fatty acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation useful as a medicine, an agrochemical, a fertilizer, etc., and having good storage stability, even when a glycerol fatty acid ester is used, by using the glycerol fatty acid ester containing strongly heated residues originated from metals in a specific amount or less as a base material for the sustained release preparation. SOLUTION: This sustained release preparation uses a glycerol fatty acid ester (for example, glyceryl distearate) containing strongly heated residues originated from one or more metals in an amount of <=0.02 wt.% as a base material for the sustained release preparation. The preparation is prepared in the form of tablets, powders or pills together with a vehicle such as corn starch having been used for preparing conventional solid preparations. An active ingredient to be processed into the sustained release preparation includes indomethacin. The glycerol fatty acid ester as a base material for the sustained release preparations is used as a base material for matrix type sustained release preparations or coated on the surfaces of solid granules as a coating material for the sustained release preparations.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to sustained-release preparations such as pharmaceuticals, agricultural chemicals, fertilizers, and fragrances.

[0002]

2. Description of the Related Art Conventionally, technical information on sustained-release preparations such as pharmaceuticals, pesticides, fertilizers, and fragrances is well known.
Many products are produced and used. Many sustained-release bases used in the production of sustained-release preparations are known and easily available. Examples of those that can be used as a sustained-release base include, for example, ethyl cellulose, hydroxypropyl cellulose, aminoalkyl methacrylate copolymer RS, etc. as the polymer type, and hardened oil, paraffin, Examples include microcrystalline wax, beeswax, stearic acid, stearyl alcohol, and glycerin fatty acid esters. There is also a great deal of information on formulating and designing sustained-release preparations using these bases.

[0003]

However, it is not easy to design and manufacture a sustained-release preparation ensuring storage stability, even with the use of generally available information.
We need know-how. For example, when glycerin fatty acid ester is used as a sustained release base, there are cases where storage stability cannot be ensured. It is speculated that the reason why storage stability cannot be ensured is that glycerin fatty acid ester has various crystal forms and undergoes crystal transition during storage. For example, in the case of monoglyceride, it is an α crystal immediately after being melted and solidified, but changes to a β crystal during storage. However, due to this, storage stability cannot always be ensured, but there are cases where storage stability is sufficiently ensured. Accordingly, an object of the present invention is to provide a sustained-release preparation having good storage stability using glycerin fatty acid ester as a sustained-release base.

[0004]

Accordingly, as a result of intensive studies, the presence or absence of the use of an alkali catalyst in the process of synthesizing the glycerin fatty acid ester, in other words, the ignition residue derived from metal in the obtained glycerin fatty acid ester was determined. It has been found that the presence or absence of the compound affects the storage stability of the release rate, and the present invention has been completed. That is, the present invention relates to a sustained-release preparation characterized in that a glycerin fatty acid ester having an ignition residue derived from a metal of 0.02% by weight or less is used as a sustained-release base.

Hereinafter, the present invention will be described in detail. For the synthesis of glycerin fatty acid ester, there is a method in which glycerin and a fatty acid or a hardened oil are reacted together by heating. As long as there is no difference in the raw materials used, that is, the fatty acid composition of the glycerin fatty acid ester,
As long as there is no difference in the molar ratio between glycerin and fatty acid, there is no difference in physical properties such as melting point, specific gravity and viscosity at the time of melting depending on the use of an alkali catalyst. However, when used in sustained-release preparations, glycerin fatty acid esters using an alkali catalyst may be disadvantageous in securing the stability during storage of the release rate of the active ingredient as compared with those not used. found. For example, when an active ingredient aimed at sustained release: a spherical granule containing indomethacin is coated with glyceryl distearate to produce a sustained release granule, the active ingredient release rate from the granule is preserved. As for the stability, when the alkali catalyst was used, the storage stability tended to be lower than when the alkali catalyst was not used.

[0006] As a result of scrutiny of glyceryl distearate, it was found that there was a difference in the ignition residue derived from metals depending on the use of an alkali catalyst as described above. That is, the ignition residue of glyceryl distearate synthesized using an alkali catalyst was 0.1% by weight, and that without an alkali catalyst was 0.02% by weight. The glycerin fatty acid ester used in the present invention can be used for sustained-release preparations, and has a metal-derived ignition residue of 0.0%.
There is no particular limitation as long as it is 2% by weight or less. For example, the constituent fatty acids include palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, myristic acid, lauric acid, ricinoleic acid, caprylic acid, behenic acid, and the like, and a mixture thereof may be used. The constituent molar ratio of glycerin and fatty acid is not particularly limited. Further, a mixture of the above-mentioned glycerin fatty acid esters may be used.

[0007] The sustained-release preparation using the glycerin fatty acid ester of the present invention is a substance generally used in the production of solid preparations, for example, corn starch, potato starch, lactose, sucrose, mannitol, talc, kaolin, sulfuric acid. Excipients such as calcium, calcium carbonate, crystalline cellulose, lubricating agents such as magnesium stearate, calcium stearate, disintegrating agents such as carboxymethylcellulose calcium, low-substituted hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone , Gelatin, gum arabic powder, binders such as polyvinyl alcohol, other colorants, antioxidants, flavoring agents, adsorbents, preservatives, wetting agents, antistatic agents, disintegration extenders, etc., or feed, fertilizer Such as a limited substance used is not the sole, it is produced by forming the solid particles form a combination of these. At that time, the sustained-release preparation can be formed into any form such as tablet, powder, granule, trickle, pellet, pill, hard capsule, and soft capsule.

The active ingredient for sustained release is not particularly limited. For example, analgesic and anti-inflammatory agents such as indomethacin, ibuprofen, ketoprofen, acetaminophen, aspirin and isopropylantipyrine, for example, diphenylpyralin hydrochloride, chlorpheniramine maleate, cimetidine , Antihistamines such as isotipendyl hydrochloride, cardiovascular agents such as phenylephrine hydrochloride, propranolol hydrochloride, procainamide hydrochloride, quinidine sulfate, isosorbide, etc. Antibiotics such as peptides or peptides such as insulin, vasopressin, interferon, interleukin 2, urokinase or human growth hormone; Park, theophylline, caffeine, citric acid Cal solid pentane, drugs such as phenylpropanolamine hydrochloride, allethrin I, Fenotorochion, insecticides, such as phenothrin, and chemical fertilizers, such as phosphoric acid.

Examples of the mode of using the glycerin fatty acid ester as a sustained-release base include using it as a base for a matrix-type sustained-release preparation or coating a solid particle surface as a sustained-release film agent. . In any case, the form present in the preparation is not particularly limited. In the manufacturing process of the formulation, the method of dissolving the glycerin fatty acid ester in an organic solvent and adding and drying may be used, the method of heating and adding it in a molten state and cooling may be used, or the method of heating after adding in a solid state may be used. well,
The method for producing the sustained-release preparation is not particularly limited. The amount of the glycerin fatty acid ester in the preparation is not strictly limited, and the type of the drug, the shape and size of the sustained-release preparation,
It can vary depending on the manufacturing method and the like.

[0010]

EXAMPLES Next, the present invention will be described more specifically with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited thereto. (Reference Examples 1 and 2) The following materials were placed in a 1-liter four-necked flask, reacted at 200 to 250 ° C. for 1 hour under a nitrogen stream, and treated in a conventional manner to obtain glycerin distearate. In addition, it repeated twice on the same conditions. Charged contents: Stearic acid 600 g (2 mol) Glycerin 100 g (1 mol) (Reference Examples 3 and 4) The following raw materials were charged into a 1-liter four-necked flask and reacted at 200 to 250 ° C. for 1 hour in a nitrogen gas flow. The resultant was treated in a conventional manner to obtain glycerin distearate. In addition, it repeated twice on the same conditions. Charged contents: Stearic acid 600 g (2 mol) Glycerin 100 g (1 mol) NaOH 0.7 g (as an alkali catalyst)

[0011]

[Table 1]

(Examples 1 and 2 and Comparative Examples 1 and 2) Pharmaceutical preparations of 24 to 32 mesh by the tumbling granulation method 59 parts of sucrose / starch spherical granules {Nonparel-101 Freund Sangyo Co., Ltd.} A mixture of 20 parts of indomethacin in Japan (pulverized with an air current mill Jet-O-Miser), 16 parts of corn starch, 1 part of carmellose calcium, and 2 parts of talc while spraying a 10% ethanol solution of 2 parts of povidone The product was sprayed slowly. This operation produced 18-30 mesh indomethacin-containing spherical granules. CF-granulator (CF-
Using 360), 2.0 g of melted normal paraffin (melting point: 66-68 ° C, Wako Pure Chemical Industries, Ltd.) was charged with 2.0 kg of the indomethacin-containing spherical granules prepared above, and 200 g of the melted Atmax was manufactured by Shizuto Kyoritsu Shokai. Using a (registered trademark) CN-200 type nozzle, normal paraffin in a molten state together with heated and pressurized air was spray-coated on granules in a rolling state. More continuously,
Spray coating was performed with a melt mixture of 38.8 g of glyceryl distearate shown in Table 2 and 1.2 g of Sun Fat PS-68 (polyglycerol fatty acid ester Taiyo Kagaku Co., Ltd.). It should be noted that there was no difference between the working example and the comparative example in workability and product appearance.

[0013]

[Table 2]

Test Examples 1-4 The preparations obtained in Examples 1 and 2 and Comparative Examples 1 and 2 were put in glass bottles and stored at 37 ° C. for one month. The indomethacin release from the formulation was evaluated before and after storage. The release method was evaluated by the rotating bottle method (Journal of Pharmaceutical Science vol.51, No.2, 1).
81-184 (1962)), the test was carried out in an artificial gastric juice (pH 1.2) containing pepsin for up to 1.5 hours, after which the solution was switched to an artificial gas containing pancreatin. The test was performed in intestinal fluid (pH 7.5). The release rate was determined by quantifying the amount remaining in the preparation. As a result, the stability of release properties of the preparations manufactured in Examples 1 and 2 was clearly stable as compared with the preparations manufactured in Comparative Examples 1 and 2.

[0015]

[Table 3]

[0016]

Industrial Applicability According to the present invention, a sustained-release preparation having a preservation stability even when a glycerin fatty acid ester is used as a sustained-release base can be obtained.

Claims (1)

[Claims] (1) A sustained-release preparation characterized in that a glycerin fatty acid ester having an ignition residue derived from a metal of 0.02% by weight or less is used as a sustained-release base.