JPH0113447B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing sustained release powder or granules in which drug elution is controlled. In detail, the coating polymer contains animal oils and fats, vegetable oils, hydrogenated oils, mineral oils, fatty acids, polyhydric alcohols, fatty acid esters, higher alcohols,
The present invention relates to a method for producing sustained-release powder or granules in which drug elution is controlled by containing a substance selected from waxes and surfactants, or a mixture thereof. Research into sustained-release drugs, particularly sustained-release pharmaceuticals, has been progressing in recent years with the aim of reducing the side effects of drugs, maintaining effective blood concentrations, and reducing the number of administrations. Generally, the drug is coated with a polymer to delay its elution. However, in conventional sustained-release powders, the elution of the coated drug has been controlled by utilizing the chemical and physical properties of the polymer or by changing the coating ratio of the polymer to the drug. It's nothing more than that. Therefore, it has been difficult to obtain a coated drug with low dissolution properties, and it has been difficult to obtain a coated drug with low dissolution properties. The present inventors selected from animal oils, vegetable oils, hydrogenated oils, mineral oils, fatty acids, polyhydric alcohols, higher alcohols, fatty acid esters, waxes, and surfactants as elution modifiers in the coating polymer. Utility in the manufacturing process, in that elution can be controlled by including substances or mixtures thereof, and phase separation of the polymer is facilitated when added before phase separation in the manufacturing process. I also found out. As a result, sustained-release powders were obtained in which the time rate of elution could be varied even if the same polymer was coated at a fixed ratio to the drug, and one with low elution properties was also easily obtained. This made it possible to complete the present invention. Therefore, an object of the present invention is to provide a method for producing a novel sustained-release powder or granule in which drug elution is controlled. The elution regulator as used in the present invention does not matter whether it is soluble or insoluble in the solvent in which the polymer is dissolved. Examples of elution modifiers include the following. Namely, animal fats and oils such as gay oil, beef tallow and lard, vegetable oils and fats such as soybean oil, sesame oil, castor oil and cacao butter, hydrogenated oils, mineral oils such as paraffin, stearic acid, oleic acid, palmitic acid, linoleic acid, etc. fatty acids, polyhydric alcohols such as glycerin, propylene glycol, and polyethylene glycol, higher alcohols such as lauryl alcohol, cetyl alcohol, and stearyl alcohol, fatty acid esters such as glycerin monostearate and glycerin tripalmitate, carnauba wax, serraz wax, beeswax, and gay wax. Preferred examples include waxes and surfactants such as animal oils, vegetable oils, hydrogenated oils, mineral oils, polyalkylene glycols, and waxes. The coating polymer as used in the present invention includes polymers that phase separate when a non-solvent for the polymer is added to a solution containing the coated polymer, and mixtures thereof.
Such polymers include ethyl cellulose, benzyl cellulose, propyl cellulose derivatives, polyvinyl acetate, polyethylene, styrene maleic acid polymers and similar homopolymers, copolymers, and the like. Solvents (good solvents) that dissolve these polymers include methylene chloride, trichloroethylene, benzene, xylene, toluene, ethanol, and acetone. Further, the non-solvent refers to a solvent in which the polymer is difficult to dissolve or does not dissolve, and includes n-hexane, cyclohexane, isopropyl ether, ethyl acetate, ethyl ether, propanol, ethanol, petroleum ether, polybutadiene, and the like. However, the good solvent and non-solvent must be mutually compatible, and both must be inert to the drug to be coated. Preferred examples of combinations of the above-mentioned coating polymer, good solvent and non-solvent are shown below.

【table】

[Table] The drugs used in the present invention include pharmaceuticals, agricultural chemicals, and others, and their forms do not matter whether they are solid or liquid. The term "liquid" refers to something that is liquid at room temperature or solid at room temperature, but also means something that is liquefied by being dissolved in a solvent. The solid and liquid particles must be substantially inert to good solvents and non-solvents for the polymer. Examples of medications include aspirin, indomethacin, diclofenac sodium, flurbiprofen,
Nonsteroidal anti-inflammatory drugs such as ibuprofen, antibiotics such as ampicillin and cephalexin, anticancer drugs, steroid hormones, antihypertensive drugs,
Potassium preparations and other drugs that require sustained release to reduce side effects and maintain effects are preferred. In addition, it can be particularly preferably applied not only to medicines but also to products such as agricultural chemicals that aim to maintain their effects. Examples of the method for producing the sustained release powder of the present invention include the following methods, depending on the timing of addition of the dissolution regulator. (1) After dispersing drug particles in a dissolution modifier, this is added to a solution in which a polymer is dissolved, and then a nonsolvent is added. (2) Drug particles are dispersed in a solution containing a polymer, a dissolution modifier is added thereto, and then a nonsolvent is added. (3) Drug particles are dispersed in a solution containing a polymer, a non-solvent is added thereto, and an elution modifier is added after phase separation of the polymer. (4) A nonsolvent and a dissolution modifier are added alternately to the polymer solution in which drug particles are dispersed. The above-mentioned “dispersing drug particles” means:
This indicates that the drug is not dissolved in a solution, but is in a kind of suspended state. Through these operations, powder particles containing the drug particles and the elution modifier incorporated in the polymer are separated in the nonsolvent. Finally, by drying this, the desired granular material can be obtained. However, the timing of addition of the elution regulator is not limited to the above. Further, as the drying method, any convenient method such as room temperature or spray drying can be selected as appropriate. The elution control agent is more effective if it is soluble in the solvent that dissolves the polymer or if it can be dispersed in the form of fine particles.The amount of the elution control agent to be added may be such that the expected elution properties are obtained, but it is preferable to against
It is 0.05-50%. Note that when a dissolution modifier that is insoluble in a solvent that dissolves the polymer is used, for example, liquid paraffin for acetone prevents the coated drug from adhering to each other, making it easy to take out as uniform particles. The dissolution properties of the sustained release powder obtained by the present invention can be adjusted over a wide range by changing the type and amount of the dissolution regulator. Next, examples of the dissolution properties of the sustained release powder obtained by the present invention will be given. (1) Ethylcellulose-coated sustained-release powder of aspirin containing liquid paraffin as a dissolution regulator (prepared according to Example 1). The dissolution test is performed using the paddle method as an eluent.
This was carried out by quantitatively quantifying eluted aspirin over time using 0.5M acetic acid-sodium acetate (PH4.5). The results are shown in Table 1.

[Table] (2) Ethylcellulose-coated sustained release powder of indomesacin containing beeswax as a dissolution regulator (prepared according to Example 2). The dissolution test was carried out by the paddle method, using a mixture of water and Japanese Pharmacopoeia 2nd solution (4:1) as the eluent, and quantifying indomethacin eluted over time. The results are shown in Table 2.

【table】

[Table] As shown in Tables 1 and 2, the sustained release powder obtained by the present invention has a controlled dissolution rate compared to conventional sustained release powder, and the dissolution rate of the sustained release powder is controlled. The elution is appropriately controlled depending on the type and amount added. The sustained release powder of the present invention has the general characteristics of coated particles: (1) color masking of substances that easily react with each other, (2) protection from outside air, and (3) odor, taste, and color masking. (4) This does not impair the advantages such as ease of handling irritating substances. When the sustained release powder or granule of the present invention contains a drug,
Needless to say, it can be used in various solid preparations such as granules and capsules. EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. Example 1 Dissolve 2 g of ethyl cellulose in 50 ml of toluene. Disperse 1 g of aspirin in the solution and add 20 ml or 40 ml of liquid paraffin as an elution modifier.
To this, 100 ml of n-hexane is added dropwise, and the ethylcellulose-rich phase separates and coats the aspirin. The coated particles are dried in a suspended state using a blade dryer to obtain sustained-release aspirin granules coated with ethylcellulose containing liquid paraffin as a dissolution modifier. Example 2 Dissolve 1 g of ethyl cellulose in 50 ml of benzene. Disperse 1 g of indomethacin in this solution. The ethylcellulose-rich phase was separated with 100 ml of n-hexane, coated with indomethacin, and then 1 g or 2 g of beeswax, an elution modifier, was added.
Add g and dissolve. When drying is carried out according to Example 1, sustained release powder of indomethacin coated with ethylcellulose containing beeswax as a dissolution regulator is obtained. Example 3 Dissolve 1 g of ethyl cellulose in 50 ml of acetone. Disperse 1 g of potassium chloride in this solution.
Next, 120 ml of a mixture of n-hexane and olive oil (volume ratio 5:1) is added dropwise to cover the potassium chloride. Here, olive oil is a dissolution modifier.
When drying is carried out based on Example 1, ethyl cellulose-coated potassium chloride sustained release powder and granules containing olive oil as a dissolution regulator are obtained. Example 4 2 g of styrene maleic acid copolymer is dissolved in 40 ml of ethanol. 10 ml of propylene glycol 1500, an elution regulator, and 1 part methylprednisolone.
g is dispersed and added to the polymer solution. Then 80 ml of isopropyl ether are added dropwise and the polymer-rich phase separates and coats the methylprednisolone. When the coated particles are separated and dried at room temperature,
A methylprednisolone sustained release powder coated with a styrene-maleic acid copolymer containing propylene glycol 1500 as a dissolution regulator is obtained. Example 5 The sustained release powder of the present invention obtained in the above example was cut and its cross section was observed under a microscope to confirm that the dissolution regulator and drug were incorporated into the polymer. did. As an example, a cross-sectional sketch of the powder obtained in Example 1 is shown in FIG.

[Brief explanation of drawings]

FIG. 1 shows a sketch of the cross-section of an ethyl cellulose-coated aspirin sustained-release powder containing 20 ml of liquid paraffin as a dissolution regulator, observed under a microscope. A: aspirin particles, B: liquid paraffin particles, C: ethyl cellulose.

Claims (1)

[Claims] 1. After dispersing the drug in a solution of a polymer selected from ethylcellulose, benzylcellulose, propylcellulose, polyvinyl acetate, polyethylene, styrene maleic acid polymer, and similar homopolymers and copolymers, In the process of adding a non-solvent for the polymer to coat the drug with the polymer, as a dissolution modifier,
A novel sustained-release powder with controlled elution of a drug, characterized by dispersing a substance selected from animal fats, vegetable oils, hydrogenated oils, mineral oils, polyalkylene glycols, and waxes, or a mixture thereof. How the body is manufactured.