JPH0587488B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to sustained release preparations for poorly soluble drugs and methods for producing the same. Many methods are conventionally known for producing sustained release preparations. However, the solubility in the gastrointestinal tract and the site of absorption of the main drug contained in the drug differ depending on its properties, so in order to obtain the blood concentration curve required for each drug, it is necessary to find the optimal formulation method for that drug. It is necessary to use Poorly soluble drugs with low solubility in water have poor absorption from the gastrointestinal tract when administered orally, and therefore have low bioavailability when administered as solid preparations. In addition, the bioefficiency of such poorly soluble drugs tends to vary depending on the manufacturing method of the preparation, and even if the preparation is immersed in gastric fluid or intestinal fluid for a long time,
In some cases, 100% of the medicinal ingredients may not be completely eluted.
It is said to be a drug that requires a dissolution test as a quality test. For example, in the case of tablets, the elution and diffusion of medicinal ingredients into the digestive juices takes place through the micropores of the solid preparation matrix, so slight fluctuations in molding pressure change the micropore diameter, causing an increase or decrease in the dissolution rate. Therefore, it is necessary to strictly control the molding pressure during manufacturing.
On the other hand, in sustained-release preparations obtained by embedding drugs in release delaying agents such as wax,
The rate of disintegration due to permeation of digestive juices is slow, which delays the onset of medicinal efficacy, but the elution of the medicinal ingredients contained therein is not 100%, and a decline in the dissolution rate is unavoidable. These tendencies become even stronger in tablets made by compression molding of matrix formulations in which poorly soluble drugs are dispersed and granulated in a mixed solution of a release retardant dissolved in an organic solvent. elution is not complete, and 100% tends not to be eluted. When this tablet is administered to humans, it does not disintegrate and is excreted in its original form, and it takes time for absorption to begin after administration, resulting in a slow increase in blood concentration and non-sustainability at the same dose. It has drawbacks such as significantly lower absorption rate than pharmaceutical preparations. If these phenomena are avoided, the drug release will be transient and the sustained effect will be insufficient. The present inventors conducted various studies in order to obtain a sustained release preparation for a poorly soluble drug that can eliminate the drawbacks of conventional methods, can reliably control the release of a poorly soluble drug, and is easy to manufacture. As a result, poorly soluble drugs,
It was discovered that a formulation that combines a release-inhibiting substance and a swelling polymeric substance at a certain ratio releases a poorly soluble drug over a long period of time, and exhibits complete dissolution with a dissolution rate of almost 100%. Ta. The present invention provides that, in a preparation containing isosorbide nitrate, prazosin hydrochloride, or furosemide (hereinafter referred to as a poorly soluble drug), (a) ethyl cellulose, acrylic acid/methacrylic acid ester copolymer, hydrogenated oil, and/or wax and (b) 0.5 to 20% by weight of a swellable polymeric substance consisting of microcrystalline cellulose coated with carboxyvinyl polymer, low-substituted hydroxypropyl cellulose, and/or sodium carboxymethylcellulose. This is a sustained release formulation of a poorly soluble drug. The preparation of the present invention can be obtained by, for example, adding and mixing a release inhibiting substance and an organic solvent to a mixed powder of a poorly soluble drug and a swelling polymeric substance, granulating the resulting mixture, and then removing the organic solvent. It will be done. Preferably, the preparation of the present invention is made into a tablet by compression molding the granules. When this compressed product is orally administered to humans, it gradually disintegrates in the gastrointestinal tract and remains in the form of granules, slowly releasing the drug. In this preparation, a water-insoluble, water-permeable or water-repellent release-inhibiting substance and a swelling polymer substance that has swelling and binding properties act appropriately on poorly soluble drugs to release the drug. Almost 100% of the contained drug is eluted while controlling the This preparation is a new poorly soluble drug preparation, and its sustained release effect is extremely excellent. The poorly soluble drug of the present invention has a solubility in water that is defined in the Japanese Pharmacopoeia as "almost insoluble (1 g of solute
10,000ml or more), including isosorbide nitrate, prazosin hydrochloride,
Examples include furosemide. The release inhibiting substance used in the present invention is a film-forming polymeric substance, and includes ethyl cellulose, acrylic acid/methacrylic acid ester copolymer, hydrogenated oil, and wax. Particularly preferred are ethyl cellulose, acrylic acid/methacrylic acid ester copolymer, etc. which are soluble in ethyl alcohol and whose solubility does not depend on pH. Ethyl cellulose is preferably one having a viscosity of 5 to 100 cps at 20°C (ethoxy group content 44 to 51% by weight), particularly one having a viscosity of 50 cps at 25°C (ethoxy group content 48 to 49% by weight). Examples of acrylic acid/methacrylic acid ester copolymers include Eudragit RL, Eudragit RL,
Something like Eudragit RS is preferable. The hydrogenated oil or wax preferably has a melting point of 50 to 90°C and is highly soluble in ethanol. Hydrogenated oils are hydrogenated vegetable oils or hydrogenated animal oils. Preferred waxes include mineral waxes such as paraffin wax, petroleum wax, Utah wax, and Montan wax, insect waxes such as beeswax and white beeswax, and vegetable waxes such as carnauba wax and tree wax. These release inhibiting substances can also be used in combination. The swellable polymeric substances used in the present invention have binding properties and swelling properties, and are substances that swell upon absorption of water and form translucent gels, such as carboxyvinyl polymer, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose. Examples include microcrystalline cellulose coated with sodium. Examples of carboxyvinyl polymers include Carbopol and Hiviswako, which are polymerized acrylic acids. Examples of low-substituted hydroxypropyl cellulose include low-substituted hydroxypropyl cellulose described in the local government regulations, and microcrystalline cellulose coated with sodium carboxymethyl cellulose. Examples include Avicel RC and Avicel RC591-NF (manufactured by Asahi Kasei Corporation). The organic solvent may be any solvent as long as it is volatile, non-reactive with poorly soluble drugs, and capable of dissolving the release-inhibiting substance. Examples of solvents that meet these conditions include methylene chloride, chloroform, methyl ethyl ketone, acetone, methyl alcohol, and ethyl alcohol. Ethyl alcohol is most preferred as it is less toxic. When producing the formulation of the present invention, first a liquid mixture of a release inhibiting substance and an organic solvent is prepared. A swellable polymer substance, a poorly soluble drug, and optional additives are added to this mixture and mixed with stirring, and the resulting mixture is granulated by an appropriate means and the organic solvent is evaporated. Although stirring and mixing may be carried out at room temperature, it is preferable to heat the mixture to 40 to 70°C. Processing time is usually 10-60
It is a minute. Granulation can be performed using a vacuum granulator, a spray dryer, and a centrifugal fluid granulator. However, after preparing the organic solvent of the mixture, it is preferable to granulate it by a wet granulation method which is easy to operate and does not require expensive equipment, and then dried to form granules. The obtained granules are compression molded by a conventional method. At this time, non-sustained release powder or granules may be added to the sustained-release granules and compression molded. The amount of release inhibiting substance is 5-80%, preferably 10-60% by weight of the formulation. The amount of swellable polymeric material is 0.5-20%, preferably 1-10% by weight of the formulation. The amount of solvent may be any amount that can dissolve the release-suppressing substance. As additives, those commonly used in orally administered preparations, such as excipients, plasticizers, binders, lubricants, coloring agents, and flavoring/flavoring agents, can be used. Excipients include lactose, starch, sucrose, crystalline cellulose, talc, etc. Binders include starch, hydroxypropyl cellulose, methyl cellulose, gelatin, etc. Lubricants include talc,
Magnesium stearate, silicic anhydride, etc. are used. The formulation of the present invention has little change in release rate due to variations in the size of granules, preparation method, hardness of compression molded product, etc., and therefore has extremely good reproducibility of release rate, making it suitable for mass production. Example 1 To 110 g of isosorbide nitrate, 310 g of lactose, 150 g of potato starch, 100 g of crystalline cellulose, and 80 g of carboxyvinyl polymer (Carbopol 934, manufactured by Gutsudoritsu) are added and mixed well with a mixer.
Next, a solution of 50 g of acrylic acid/methacrylic acid ester copolymer (Eudragit RS, manufactured by Rohm and Haas) and 200 g of hydrogenated oil is added to 50 ml of warm ethanol, and the mixture is stirred and kneaded at 55 to 60° C. for 10 minutes. This kneaded product was granulated using a pelletizer, dried, and sized to obtain sustained release granules of 16 to 32 meshes. 1 g of talc as a lubricant, 0.5 g of silicic anhydride and 0.5 g of hydrogenated oil were added to 98 g of the granules and mixed to obtain compression molded tablets A (total weight 190 mg) each containing 20 mg of isosorbide nitrate. Example 2 200 g of isosorbide nitrate, 300 g of lactose and 60 g of carboxyvinyl polymer (Carbopol 934)
Add and mix well with a mixer. Next, add 50 g of ethyl cellulose and 390 g of hydrogenated oil to 450 ml of warm ethanol.
Add the solution containing g and stir and knead at 55-60°C for 30 minutes. This kneaded product was granulated, dried, and sized to obtain sustained release granules. 10 g of carboxymethyl cellulose calcium, 1 g of talc and 1 g of magnesium stearate were added to 88 g of this granular material and mixed.
Compression-molded tablets B (total weight 230 mg) containing 40 mg of isosorbide nitrate per tablet were obtained. Example 3 44 g of the sustained release granules of Example 2, 44 g of the following isosorbide nitrate immediate release granules, 1 g of talc and 1 g of magnesium stearate as lubricants were mixed to form a compressed tablet containing 40 mg of isosorbide nitrate per tablet. Molded tablets C (total weight 210 mg) were obtained. Isosorbide nitrate immediate release granules: Add 63 parts of lactose, 10 parts of potato starch, and 5 parts of crystalline cellulose to 20 parts of isosorbide nitrate and mix well. Then hydroxypropyl cellulose 2
40 parts of water/alcohol solution containing 16 to 32 parts was added, kneaded, granulated, dried, and sized to obtain granules (16 to 32 parts).
particle size distribution). Example 4 250 g of isosorbide nitrate, 450 g of lactose, carboxyvinyl polymer (Hibis Wako manufactured by Wako Pure Chemical Industries, Ltd.)
Add 50 g of 104) and 50 g of low-substituted hydroxypropyl cellulose (L-HPC manufactured by Shin-Etsu Chemical Co., Ltd.) and mix well with a mixer. Then warm ethanol
Add a solution of 50 g of ethyl cellulose and 150 g of hydrogenated oil to 500 ml, and stir and knead. This kneaded product was granulated using a pelletizer, dried, and sized to obtain sustained-release granules. 1 g of talc and 1 g of magnesium stearate as lubricants were added to 98 g of this granular material and mixed, and 40 mg of isosorbide nitrate was added per tablet.
Compression molded tablets D (total weight 165 mg) were obtained. Example 5 Using 22 g of prazosin hydrochloride, 578 g of lactose, 150 g of potato starch, 100 g of crystalline cellulose, 30 g of carboxyvinyl polymer, 20 g of ethyl cellulose dissolved in warm ethanol and 100 g of hydrogenated oil, and otherwise operating in the same manner as in Example 1, Sustained release granules of prazosin hydrochloride were obtained. To 98g of this granular material, 1g of talc and 1g of magnesium stearate as a lubricant.
Add 2 g of prazosin hydrochloride per tablet and mix.
A compression-molded tablet E (total weight 100 mg) containing 100 mg was obtained. Example 6 52 g of the prazosin hydrochloride sustained release granules of Example 5 were mixed with 36 g of the following prazosin hydrochloride immediate release granules, 1 g of talc and 1 g of magnesium stearate as lubricants, and each tablet contained 2 mg of prazosin hydrochloride. Compression-molded tablets F (total weight 100 mg) were obtained. Prazosin hydrochloride rapid granules: Add 70.8 parts of lactose, 15 parts of potato starch, and 10 parts of crystalline cellulose to 2.2 parts of prazosin hydrochloride and mix well. Then add 40 parts of a water/alcoholic solution containing 2 parts of hydroxypropyl cellulose,
Kneaded, granulated, dried, and sized to make granules (16~
32 particle size distribution). Example 7 Furosemide 200g, lactose 240g, potato starch
Using 100 g of microcrystalline cellulose, 50 g of crystalline cellulose, 40 g of carboxyvinyl polymer, 70 g of ethyl cellulose dissolved in warm ethanol, and 300 g of hydrogenated oil, the other procedures were the same as in Example 1 to obtain sustained release granules of furosemide. 5 g of carboxymethyl cellulose, 1 g of talc, and 1 g of magnesium stearate were added to 93 g of this granular material and mixed. Compression molded tablets G containing 40 mg of furosemide per tablet (total weight 220 mg)
I got it. Test Example 1 A dissolution test was conducted by applying the dissolution test method 1 described in Japanese Pharmacopoeia X, the rotating basket method. First, one compression-molded tablet was taken as a specimen, placed in a basket, immersed in 900 ml of test solution adjusted to pH 1.2, and rotated at 150 rpm for 2 hours. Then, after gently lifting the basket, the pH was adjusted to 6.8 again.
The sample was immersed in 900 ml of a test solution adjusted to 100 ml, and rotated at 150 rpm for up to 4 hours. Test solutions were collected over time, and the amount of drug dissolved in each test solution was measured using the method described below. The results are shown in Tables 1-3. Isosorbide nitrate: High performance liquid chromatography method Prazosin hydrochloride: Fluorescence analysis method Furosemide: Absorbance measurement method

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[Table] Test Example 2 One tablet each of the compression-molded tablet C (containing 40 mg of isosorbide nitrate in one tablet) or the regular tablet S (containing 5 mg of isosorbide nitrate in one tablet) of Example 3 was orally administered to six healthy subjects, and plasma The amount of isosorbide nitrate in the mixture was determined by gas chromatography. The results are as shown in the drawings (C represents the formulation of the present invention and S represents the comparative formulation). As is clear from this, the sustained-release preparation of the present invention was found to be significantly effective in maintaining the plasma concentration of isosorbide nitrate 4 to 8 hours after administration. When this sustained-release preparation was administered, an effective plasma concentration was reached immediately after administration, and this concentration was maintained for a long period of time. In addition, when compared with regular tablets, no significant differences were observed in C _nax (maximum plasma concentration) and AUC (area under the 1-hour plasma concentration curve), and there was no significant difference in T _nax (time to reach maximum plasma concentration). A significant difference was observed. From these points, it is clear that there is no difference in the total absorption amount and that the absorption rate is not impaired. From this, in the formulation of the present invention,
It is known that the drawbacks of long-acting formulations of poorly soluble drugs, such as decreased absorption and weakened sustained effects, have been improved.

[Brief explanation of the drawing]

The figure is a graph showing the average human plasma concentration of the isosorbide nitrate preparation according to Test Example 2, where C is the preparation of the present invention and S is the comparative preparation.

Claims (1)

[Scope of Claims] 1. In a preparation containing isosorbide nitrate, prazosin hydrochloride, or furosemide, a release suppressant consisting of (a) ethyl cellulose, acrylic acid/methacrylic acid ester copolymer, hydrogenated oil, and/or wax based on the weight of the preparation A sparingly soluble material containing 5 to 80% by weight of the substance and (b) 0.5 to 20% by weight of a swellable polymeric substance consisting of microcrystalline cellulose coated with carboxyvinyl polymer, low-substituted hydroxypropyl cellulose, and/or carboxymethyl cellulose. Sustained release formulations of drugs. 2 Claim 1 in which the dosage form is a compression molded product
Extended-release formulations as described in Section. 3. Mixed powder of a swellable polymeric substance consisting of microcrystalline cellulose coated with isosorbide nitrate, prazosin hydrochloride, or furosemide and (b) carboxyvinyl polymer, low-substituted hydroxypropyl cellulose, and/or carboxymethyl cellulose, (a) ethyl cellulose, It is characterized by adding and mixing an acrylic acid/methacrylic acid ester copolymer, a release inhibiting substance consisting of hydrogenated oil and/or wax, and an organic solvent, granulating the resulting mixture, and then removing the organic solvent. 5 to 80% by weight of release inhibiting substance and swelling polymeric substance based on the weight of the formulation
A method for producing a sustained-release preparation of a poorly soluble drug containing 0.5 to 20% by weight.