WO2004073692A1

WO2004073692A1 - Hard capsule of hardly water-soluble drug

Info

Publication number: WO2004073692A1
Application number: PCT/JP2004/001751
Authority: WO
Inventors: Sennichi Kohara; Haengja Kang
Original assignee: Yamashita, Shinji
Priority date: 2003-02-18
Filing date: 2004-02-17
Publication date: 2004-09-02
Also published as: JPWO2004073692A1

Abstract

A hard capsule characterized by containing a hardly water-soluble drug, a hydrophilic solubilizing agent and a quality improving agent in which the oral absorbability of the hardly water-soluble drug is improved by improving the dissolution of the hardly water-soluble drug and which sustains excellent qualities over long-term storage.

Description

Hard capsules of poorly water-soluble drugs

Technical field

The present invention relates to hard capsules of poorly water-soluble drugs. More specifically, the present invention relates to a medicament for water repellency at a pH in the gastrointestinal tract of 1.2 to 8.0 administered orally.

The present invention relates to an eighty-one capsule of a poorly water-soluble drug which not only improves solubility of a soluble drug but also has excellent quality even after long-term storage. Rice field

Background art

According to the Japanese Pharmacopoeia, a drug that is hardly soluble in water is defined as a drug having a solubility of 0.1 mg Zm1 or less (Non-Patent Document 1). Usually, orally administered drugs first dissolve in the gastrointestinal endocrine fluid, migrate to the small intestine, and are absorbed.However, when a poorly water-soluble drug is administered orally, the poorly water-soluble drug is dissolved in the gastrointestinal tract. It is easily analogized and often observed that stool is excreted without being sufficiently absorbed because it does not dissolve in the urine. Many pharmaceutical studies have been made to improve oral solubility by improving the solubility of this poorly water-soluble drug (Non-Patent Document 2). For example, there have been reports of treatment methods that maintain the bulk solids, such as finer powders of poorly water-soluble drugs, polymorphism, amorphization, formation of salts and solvates, etc. This is a method of improving dissolution rate rather than solubility, and there is a limit in improving oral absorbability. Even if a promising treatment method could be found, a great deal of labor was needed in subsequent industrialization studies and quality control.

On the other hand, as a method for improving the apparent solubility of a poorly water-soluble drug, a solubilization method using a hydrophilic solubilizing agent such as polyethylene glycol has been reported. example For example, it has been reported that poorly water-soluble digoxin solubilized with low-molecular-weight polyethylene dalicol exhibits an oral absorption approximately twice as high as that of its tablet (Non-Patent Document 3). In addition, as a solubilized system to soften or harden acidic, basic and amphoteric drugs, a high content of poorly water-soluble drugs can be obtained by adding polyethylene glycol and hydroxyl or hydrogen ions. A patent has been published that it can be solubilized and a capsule can be prepared, but only the dissolution rate of tablets and PH 7 is compared to improve the solubility of the solubilized formulation of ibuprofen. No comment is made on the solubility at pH 1.2 or 8.0, which is the pH in the digestive tract (Patent Document 1).

On the other hand, in the solubilization method using polyethylene glycol, the poorly water-soluble drug is apparently dissolved in a test tube, but the improvement in oral absorption of the poorly water-soluble drug is not so much different from the above-mentioned treatment method. Have been. As a cause, it has been found that a drug containing a poorly water-soluble drug precipitates when orally administered and comes into contact with secretory fluid (PH 1.2 to 8.0) in the digestive tract. The essential solubilization method that leads to improvement in oral absorption is that it is also soluble in the gastrointestinal tract. Therefore, recently, a solubilization method that does not precipitate in secretions in the gastrointestinal tract has been reported. For example, Patent Document 2 discloses a drug delivery system containing 10% by weight of poorly water-soluble drugs cyclosporine, difendipine, and indomethacin by the co-solvent effect of a lipid and a surfactant to improve water solubility. It has been published. Although it has been confirmed that these solubilizing formulations do not precipitate when diluted with water, they do not specify oral formulations such as hard capsules that guarantee quality.

On the other hand, many methods for solubilization by mixing a lipophilic solubilizer such as fats and oils such as medium-chain fatty acid triglyceride and a surfactant have been reported, and for example, oils such as vitamins A, D, and E-cyclosporine can be easily prepared. Although these drugs have been applied to dissolving drugs, these preparations are basically orally administered and then emulsified in the digestive tract by emulsification, absorbed into the lymph due to the large particles of the emulsion, and then into the body. Sucking Although it is known to be absorbed, the absorption efficiency is poor compared to normal absorption, and oral absorption is often reduced for drugs with strong affinity for fats and oils. Furthermore, few drugs are dissolved by fats and oils alone.

In addition, recently, approximately 15% by weight of cyclosporine, an immunosuppressant, and a solubilizing agent and a surfactant were blended to increase water solubility, and did not precipitate in the gastrointestinal tract after oral administration. A gelatin soft capsule (Neoral (registered trademark)) with a small amount and improved oral absorption is on the market (Non-Patent Document 4). Similarly, for amprenavir which is an anti-AIDS agent, (a) 15% by weight of amprenavir, (b) polyethylene glycol and a small amount of propylene glycol as a hydrophilic solubilizer, and (c) a surfactant A soft gelatinous softener containing vitamin E succinate and polyethylene glycol 1000 ester is commercially available.

In addition to gelatin soft capsules, gelatin hard capsules have been proposed. For example, a sustained-release hard capsule filled with a semisolid oil-based suspension matrix in which captopril is simply suspended in an oil or fat is commercially available (Non-Patent Document 5). However, this formulation is a sustained-release formulation and is poorly soluble in water. It is not a capsule that improves the solubility of sex drugs.

[Non-Patent Document 1]

"The 14th Revision of the Japanese Pharmacopoeia", Hirokawa Shoten, June 2001, A14 [Non-Patent Document 2]

Mitsuru Hashimoto, “Prescribing Design of Oral Preparations”, Jiho, April 1998, p.

73-75, p.164-166

[Non-Patent Document 3]

E. Astorri, et.al., Bioavailability and related heart function index of digoxin capsules and t blets in cardiac patients ", Journal of Pharmaceutical Sciences, vol. 68, p. 104, 1979.

[Non-Patent Document 4] WA Ritschel, "Microemulsion technology in the reformulation of cyclosporin; The reason behind the pharmacokinetic properties of Neoral (R)", Clin- Transplant, vol.10, No., p.364-373, 1996

[Non-Patent Document 5]

Y. Seta, et.al., "Design and preparation of captopril sustained- release dosage forms and their biopharmaceutical properties", International Journal of Pharmacognosy, vol.41, p.245-254, 1988

[Patent Document 1]

US Patent 5360615

[Patent Document 2]

WO 99/56727 Pamphlet Disclosure of the Invention

To improve oral absorption of poorly water-soluble drugs, a solubilization method that does not precipitate even in secretions in the digestive tract is required. On the other hand, recently poorly water-soluble drugs have the property that they are hardly soluble in oil as well as in water, so they are often insoluble by conventional solubilizers alone. In addition, even if a poorly water-soluble drug can be solubilized by a hydrophilic solubilizer, filling the hard capsule usually causes the hard capsule to dissolve, leak, deform, crack, etc., and it is known that the quality is not maintained for a long period of time. ing. Therefore, there is a need for a solid preparation for oral administration that maintains its quality for a long period of time even if it contains such a hydrophilic solubilizing agent.

In the past, the only way to formulate a solubilizing formulation, including the two formulations of cyclosporine and amprenavir described above, was to fill gelatin soft capsules. However, soft capsules have a problem that they can be applied only to low-viscosity drug solutions due to the manufacturing method of molding a sheet of molten gelatin into a soft capsule and filling the drug solution at the same time. In addition, soft capsules Since the film contains a large amount of plasticizers such as gelatin and glycerin, which are main components, there is also a problem that the film is more susceptible to environmental humidity than hard capsules. For example, if a soft capsule absorbs moisture, it will soften, deform, or stick. When the water content is low, it is easily broken and causes liquid leakage. In addition, the skin usually needs to have 6 to 10% moisture because it becomes brittle when placed in a cold place. In addition, propylene dalicol, which is a strong hydrophilic solubilizing agent and a plasticizer, may adversely affect the skin, and may degrade gelatin. Recently, the risk of using gelatin derived from animals such as cattle has been regarded as a problem from the viewpoint of mad cow disease, and it is desired to avoid soft gelatin capsules with a large amount of gelatin. I have.

On the other hand, hard capsules have been provided with vegetable or synthetic polymer hard capsules instead of gelatin. In addition to the technological innovation of filling machines and sealing machines to prevent liquid leakage from the joint between the cap and the body, the enhancement of peripheral equipment such as heating equipment will enable filling of high viscosity chemicals. In contrast, soft capsules can be manufactured more easily and soft capsules can only produce a liquid solubilizing formulation, but not only liquid but also semi-solid solubilizing formulations can be manufactured. However, the hard capsule itself is hardly affected by the humidity of the environment, but because of its thin film thickness and greatly affected by the contents to be filled, especially the solubilizing agent, the solubilization is more permissive than the soft gelatin capsule. The type of agent is limited. For example, it is known that even low molecular weight polyethylene dalicol, which is permitted in soft capsules, not only denatures gelatin in hard capsules but also leaks and deforms.

In view of the above situation, the present inventors have searched for a hydrophilic solubilizer capable of solubilizing a poorly water-soluble drug at a high concentration and improved the hydrophilic solubilizer in order to improve oral absorption of a poorly water-soluble drug. Even after filling, we studied hard capsules that do not cause liquid leakage or deformation and maintain quality for a long time. However, it has been found that the quality of the hard capsule is remarkably maintained for a long period of time if a quality preservative for preventing the deterioration of the hard capsule is added to the content of the hard capsule. Specifically, the contents of a mixture of a poorly water-soluble drug, a hydrophilic solubilizing agent that can solubilize at a high concentration, and a quality preservative are filled in hard capsules, and the temperature is maintained at 40 ° C for 6 months (at room temperature for 3 years). (Accelerated test) Some observations revealed that (a) the appearance changes of the hard capsules

(b) Even in the case where there was no change in appearance, in order to observe the qualitative change of the hard capsule, the quality retention agent was used for the dissolution of acetoaminophen from the hard capsule filled with the known drug acetoaminophen. By comparing and comparing the case with and without the addition, it was found that the hard capsule with the quality preservative added clearly maintained the quality of the hard capsule. In addition, the present inventors have prepared solubilizing formulations of various poorly water-soluble drugs, and have studied the solubility and elution of a gastric juice having a pH of 1.2 and a small intestinal fluid having a pH of 6.8 in a buffer solution. As a result of examining the properties, it was found that in the hard capsule preparation of the present invention, the poorly water-soluble drug did not precipitate in the digestive tract.

That is, the present invention

(1) a poorly water-soluble drug,

(i) a surfactant or

(ii) hydrophilic solvent and surfactant

A hydrophilic solubilizer containing

A hard capsule of a sparingly water-soluble drug, characterized in that the content containing the quality preservative is filled in a capsule.

(2) The quality preserving agent is (a) purified water, (b) a thickening agent that brings the kinematic viscosity of the content to 100 to 20000 (mp as), and (c) the melting point of the content is 30 to 80 ° C. The hard capsule preparation according to the above (1), wherein the hard capsule preparation is a high melting point additive or a combination thereof. (3) The quality preservative is (a) purified water, (b) a cellulosic polymer additive or polybierpyrrolidone, or a solution obtained by dissolving and dispersing the above substance in purified water or a polyhydric alcohol or a mixture thereof. The hard capsule according to the above (1), wherein the hard capsule is at least one selected from the group consisting of (c) light caffeic anhydride, (d) a higher fatty alcohol and (e) a glycerin long-chain fatty acid ester.

(4) The hard capsule preparation according to any one of the above (1) to (3), wherein the mixture filled in the capsule has a semi-solid state or a liquid state.

(5) The hard capsule according to any of (1) to (4), wherein the hardly water-soluble drug is contained in an amount of 0.1 to 50% by weight.

(6) The hard capsule according to any one of (1) to (5), wherein the hydrophilic solubilizer is contained in an amount of 20 to 99.8% by weight,

(7) The hard capsule according to any of (1) to (6), wherein the quality preservative is contained in an amount of 0.1 to 30% by weight,

(8) The hard capsule preparation according to any one of the above (1) to (7), wherein the surfactant contains at least vitamin E succinate polyethylene ester or polyoxyethylene hydroxy fatty acid ester.

About. BEST MODE FOR CARRYING OUT THE INVENTION

The poorly water-soluble drug used in the present invention is particularly limited as long as the drug has a solubility in water, specifically, water of pH 1.2 to pH 8, which is the pH in the digestive tract, at room temperature of about 0.1 mgZml or less. Not done. The poorly water-soluble drug used in the present invention is not limited to drugs that are prescribed in the Japanese Pharmacopoeia as a drug that hardly dissolves in water, and includes, for example, compounds having biological activity, foods, especially functional foods, herbal medicines, and animals. Drugs, feeds or reagents are included. The poorly water-soluble drugs used in the present invention include, for example, drugs for central nervous system such as phenytoin, imibramine, nitrazepam, haloperidol and salts thereof, and drugs for peripheral nervous system such as indomethacin and fenylbuzone. , Ibuprofen, piroxicam and their salts, and circulating agents such as digoxin, pindolol, difludipine, reserpine, cinnarizine, probucol, clofibrate and their salts, and respiratory agents such as rebifogenin and nos. Power pins, pranlukast, zosun zolast, montelukast and their salts, etc., digestive tract drugs sofalcone, ursodeoxycholic acid, dongperidone and their salts, and hormonal agents Danazol, Ethinil Estradio , Cortisone acetate, dexamethasone and their salts, urogenital drugs furosemide, spironolactone, tribenoside and their salts, etc., and oncological drugs evening moxifen, busulfan, taxol and their salts, etc. Griseofulvin, ketoconazole, albendazole and their salts, such as antibiotics and chemotherapeutic agents, and amprenavir, nelfinavir, ritonavir, sucinavir, and their salts, which are anti-AIDS agents; And fat-soluble vitamins such as vitamins A and D or their derivatives, tocopherol acetate, etc., and ticlopidine, amiodorone, oral peramide, ketanserin, verapamil, terfenadine, trifluoroproprazin, and tolodizone. Piodari evening Zon, Ivry flavone, evening Kurori Mus, such as cyclosporin and their salts.

The hydrophilic solubilizing agent used in the present invention is not particularly limited as long as it contains (i) a surfactant or (mouth) a hydrophilic solvent and a surfactant, and those which can be orally administered are acceptable. preferable.

Examples of the surfactant include polyoxyethylene hardened castor oils such as HCO10, HCO40, HCO50, HCO60, Cremophor RH40, polyoxyl35 hardened castor oil, and polyoxyl40 hydrogenated hardened castor oil. Such Hardened castor oils such as Tween 40, Tween 60, Tween 65, Tween 80 and other polysorbates such as Labrasol®, Gelucire® 44Z14, Gelucire® 50 Polyethylene glycol 1500 fatty acid tridalicerides such as / 13, etc. Polyethylene glycol fatty acid triglycerides such as polyoxyethylene hydroxystearate (SolutolHS15 (registered trademark)), etc. Polyoxyethylene hydroxy fatty acid esters such as Imwiter (registered) (Trademark) 191, 308, 380, 742, glycerin fatty acid esters such as glycerin palmitostearate, and the like. Fatty acids are preferably fatty acids having 1 to 50 carbon atoms. In addition, for example, vitamin E polyethylene glycol esters such as vitamin E succinate polyethylene glycol 1000 ester (Tocophersolan (registered trademark)), fatty acids such as stearic acid, lauric acid, palmitic acid, and oleic acid, and salts thereof. Poloxamers, sodium lauryl sulfate and the like are also preferred. Examples of the surfactant used in the present invention include various polyoxyethylene hydrogenated castor oils, sodium lauryl sulfate, Gelucire44 / 14, vitamin E succinate polyethylene glycol 1,000 000 ester, polyoxyethylene hydroxystearate ester, and Imwiter 742. preferable. As the surfactant, those capable of solubilizing a poorly water-soluble drug in water by forming micelles with a hydrophilic solvent are preferable. Examples of the hydrophilic solvent include various polyethylene glycols such as PEG400, PEG600, PEG1000, PEG 1500, PEG 1540. Dimethyl sulfoxide, dimethylacetamide, dimethylformaldehyde, diethylene glycol ether and the like are preferable, and among them, various polyethylene glycols, propylene glycol and diethylene glycol ether are more preferable. The hydrophilic solvent is not used alone but in combination with a surfactant. For example, even if only polyethylene glycol is used as the hydrophilic solubilizer, the intended purpose cannot be achieved.

The hydrophilic solubilizer may further contain a compound that gives a counter ion to the poorly water-soluble compound, if desired. As a compound that gives a counter ion, any compound that gives a cation to an acidic drug may be used. Specifically, medalmine, diethanolamine, benzathine, and alkali metals (sodium, potassium, etc.), which are organic cations, may be used. ), Or hydroxides of alkaline earth metals (magnesium, calcium, etc.). Particularly, sodium hydroxide and potassium hydroxide are more preferable. The basic drug may be any compound that gives an anion, such as hydrochloric acid, sulfuric acid, acetic acid, bromic acid, citric acid, maleic acid, tartaric acid, methanesulfonic acid, and phosphoric acid. preferable. In particular, hydrochloric acid is more preferred. As the amphoteric drug, all of the aforementioned compounds are preferable, and particularly, sodium hydroxide, potassium hydroxide, and hydrochloric acid are more preferable. These are preferably used in the form of an aqueous solution.

The amount of the compound that gives a counter ion to the poorly water-soluble compound is preferably 0.2 to 1.2 times the molar amount of the poorly water-soluble drug. In particular, it is more preferably from 0.5 to equimolar.

As a preferred example of the hydrophilic solubilizer according to the present invention,

(1) Vitamin succinate E polyethylene glycol ester

(2) Polyoxyethylene hydroxy fatty acid ester

(3) Mixture of vitamin succinate E polyethylene glycol ester and polyethylene glycol or propylene glycol

(4) (a) Vitamin E succinate Ethylene glycol ester and (mouth) Polyethylene glycol or propylene glycol and (c) a mixture of sodium hydroxide, potassium hydroxide or hydrochloric acid

(5) (a) Polyoxyethylene hydroxy fatty acid ester and (mouth) Mixtures of render or propylene dalycol with (8) sodium hydroxide, hydroxylated water or hydrochloric acid

Preferably, sodium hydroxide, potassium hydroxide and hydrochloric acid are used as an aqueous solution having an appropriate concentration.

The quality preservative used in the present invention is not limited as long as it contributes to the chemical or physical stability of the hard capsule filled with the contents containing the hydrophilic solubilized poorly water-soluble drug. May be. Specifically, a hard capsule filled with a poorly water-soluble drug, a solubilizing agent, and a quality preservative is subjected to an accelerated test in which it is stored at 40 ° C for 6 months, and as a result, appearance damage (for example, It is preferable that substantially no deterioration in the dissolution of the drug from the capsule is observed, such as softening, dissolving, leaking, cracking and deformation). Such a hard capsule preparation of the present invention is excellent in storage stability.

Examples of the quality maintaining agent used in the present invention include purified water, a thickener, and a high melting point additive. Examples of the thickener include substances that make the kinematic viscosity of the content filled in the hard capsule about 100 to 2000 (mpas). More specifically, for example, a cell mouth-based system Preferred are polymers or polyvinylpyrrolidone, polyalginic acid, polyacrylic acid and the like. Alternatively, a liquid obtained by dissolving and dispersing the above substance in purified water or a polyhydric alcohol or a mixed solution thereof, or a light caustic anhydride or a polyalginic acid may be used. As the high melting point additive, any substance can be used as long as it is solid at around room temperature and has a high melting point. Specifically, the melting point of the content is adjusted to about 30 to 80 ^a C. No. More specifically, for example, higher fatty alcohols, glycerin long-chain fatty acid esters, high-molecular-weight polyethylene glycols (100, 150, '400, 0600, 200,000) 0), polyethylene glycol 1500 fatty acid esters or vitamin succinate E polyethylene glycol 100 ester.

As the quality preserving agent used in the present invention, (a) purified water, (b) A cellulose-based polymer or polyvinylpyrrolidone (K 25, Κ30, etc.), or a solution obtained by dissolving or dispersing the above substance in purified water or a polyhydric alcohol or a mixture thereof; (c) light caffeic anhydride; ) Higher fatty alcohols or (e) dali serine long chain fatty acid esters. The purified water may be distilled water or physiological saline, and is preferably purified water or distilled water. When the compound giving the counter ion is mixed as an aqueous solution, since water is used, it is not necessary to use a quality maintaining agent such as purified water.

When a solvent in which a cellulosic polymer additive or polyvinylpyrrolidone is dissolved or dispersed in purified water or a polyhydric alcohol or a mixture thereof is used as a solvent, such a solvent may also serve as a quality preservative. Therefore, it is not necessary to add a quality preservative.

Examples of the cellulosic polymer include hydroxypropyl cellulose, hydroxypropylmethylcellulose, and the like. Examples of the polyhydric alcohol include low-molecular-weight glycols such as ethylene glycols (ethylene glycol, diethylene glycol, triethylene glycol), glycerin, propylene glycol, 1,3-butylene glycol; and polyethylene glycol. Alternatively, high molecular weight glycols having a molecular weight of about 200 to about 6,000, such as polypropylene glycol, may be mentioned, and polyethylene glycol 400 or propylene glycol is more preferable.

Examples of the higher fatty alcohol include fatty alcohols having 16 to 22 carbon atoms, such as cetyl alcohol, stearyl alcohol and cetostearyl alcohol, and among them, cetostearyl alcohol is preferable.

The glycerin long-chain fatty acid ester refers to an ester of a long-chain fatty acid and glycerin or polyglycerin and a derivative thereof, and may be any of a monoester, a ester, a triester or a polyester. For example, esters of long-chain fatty acids and glycerin (glycerin long-chain fatty acid esters in a narrow sense), glycerin Long-chain fatty acid esters of acetic acid, glyceric acid, long-chain fatty acid esters of glycerin, glycerin lactic acid, long-chain fatty acid esters of glycerin, glycerin diacetyl tartrate, long-chain fatty acid esters of polyglycerin, and polyglycerin condensed lysylate. Examples of the long-chain fatty acids include saturated or unsaturated fatty acids having 12 to 40, preferably 12 to 22 carbon atoms. As the fatty acid, for example, stearic acid, palmitostearic acid, oleic acid, lauric acid, linoleic acid, behenic acid and the like are preferable, and palmitostearic acid is more preferable.

More preferably, the quality preservative used in the present invention is (a) purified water, (b) a cellulosic polymer additive, polybierpyrrolidone, or the like, or purified water, polyethylene glycol 400 or propylene glycol or One or more selected from the group consisting of a solution dissolved and dispersed in a mixture thereof, (c) light gay anhydride, (d) cetostearyl alcohol, and (e) glyceryl palmitostearate.

One additive may have both a role as a hydrophilic solubilizer and a role as a quality preservative, for example, higher fatty alcohols or dalyserin fatty acid esters. Purified water is most preferred as the quality preservative used in the present invention.

In the capsule of the invention according to the present invention, the content of the poorly water-soluble drug in the preparation is about 0.1% to about 50% by weight, and about 1% to about 30% by weight is more preferable. preferable. The content of the hydrophilic solubilizer in the preparation is preferably from about 20% to about 99.8% by weight, more preferably from about 50% to about 90% by weight. The content of the hydrophilic solvent in the preparation is preferably about 0.1% by weight to about 20% by weight, more preferably about 1% by weight to about 10% by weight. The content of the quality preservative in the preparation is preferably from about 0.1% to about 30% by weight, more preferably from about 1% to about 20% by weight. As a material (hereinafter, referred to as a capsule material) constituting the hard capsule according to the present invention, a known material may be used, but a material that is acceptable for oral administration is particularly preferable. Examples include agar, alginate, starch, xanthan or dextran, which are naturally occurring polysaccharides, and gelatin or zein, which is a protein. Chemically treated products include hydroxystarch, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol or derivatives thereof, polyacryl derivatives, polyvinylpyrrolidone or derivatives thereof, and polyethylene glycol. The hard capsules according to the present invention are preferably gelatin hard capsules, hydroxypropylmethylcellulose hard capsules or pullulan hard capsules, and more preferably hydroxypropylmethylcellulose hard capsules or pullulan hard capsules.

The hard capsule used in the present invention can be easily produced according to a known method. For example, a method in which a molding pin is immersed in an aqueous solution (die) in which the above-mentioned capsule material, and if desired, a gelling agent and, if desired, a gelling aid is dissolved, is lifted, is gelled, and is dried. With this, a hard capsule can be obtained.

The hard capsule obtained as described above is filled with a poorly water-soluble drug, a hydrophilic solubilizer, and a quality preservative, preferably after uniformly mixing, dissolving or dispersing them, thereby filling the capsule. The hard capsule of the invention can be obtained. In addition to the poorly water-soluble drug, the hydrophilic solubilizing agent and the quality preserving agent, other additives may be filled in the capsule, as long as the object of the present invention is not adversely affected. As the “other additives”, additives that are commonly used for the purpose according to the use of the hard capsule preparation of the present invention can be used. For example, food colors, opacifiers, viscosity modifiers Agents, gelling agents, gelling auxiliaries or excipients (eg, lactose, glucose, shonan, mannitol, etc.). In addition, it is filled in the hard capsule Substances are collectively referred to as "contents."

The method of filling the contents may be performed according to a conventional method. For example, the above-mentioned eighteen capsule (composed of a pair of a body and a cap) is set in a drug filling machine, and after separating the body and the cap, the body is filled with a certain amount of contents and the cap is connected. Such a method can be adopted. If desired, a so-called band seal microspray sealing is preferably applied to the joint between the cap and the body using the same components as the capsule material.

For example, in order to prevent liquid leakage from the joint between the body and the cap, it is preferable that after filling the contents into the body, the cap is closed and the joint is quickly fused to perform sealing. As described above, even if a hydrophilic solubilizing agent is contained, if there is only an additive that maintains the quality of hard capsules, the contents containing a poorly water-soluble drug with improved absorbability upon oral administration can be prepared. By filling in capsules, solid preparations for oral administration can be made.

The content to be filled into the hard capsule may be in any form such as liquid, semi-solid or solid (for example, powder, granule or tablet), but from the viewpoint of improving absorbability during oral administration. It is preferable that the compound has a liquid or semi-solid form.

Liquid and semi-solid contents can be obtained according to known methods. For example, the liquid content can be obtained by dissolving or dispersing a poorly water-soluble drug, a hydrophilic solubilizer, an emulsifier, a quality preservative, and other additives as required in a suitable solvent. Here, the solvent can be appropriately selected according to the use of the hard capsule preparation of the present invention. If a thickener is used as a quality preserving agent, a thickener and a thickener auxiliary agent are used at this time. You may use simultaneously. As the thickening aid, any solid cellulose-based polymer additive, a carrier capable of dissolving and dispersing polyvinylpyrrolidone, light caffeic anhydride, polyalginic acid, polyacrylic acid, etc. may be used. Alcohol, glycerin, etc. or their mixture Are preferred. Furthermore, if a high melting point additive is used as a quality preservative, a semi-solid content can be prepared. As the additive, the high melting point hydrophilic solubilizer of the present invention can also be used. For example, higher fatty alcohols, glycerin long-chain fatty acid esters, high molecular weight polyethylene glycols such as PEG1000, PEG 1500, PEG4000, PEG6000, PEG20000, polyethylene glycol 1500 fatty acid esters, or vitamin E succinate E polyethylene glycol 1000 ester Is preferred. In particular, higher fatty alcohols, glycerin long-chain fatty acid esters, high molecular weight polyethylene glycols such as PEG1000, PEG 1500, PEG 4000, PEG 6000, and PEG 20000, polyethylene glycol 1500 fatty acid esters, and vitamin E succinate E polyethylene glycol 1000 ester are more preferable.

The hard capsule preparation of the present invention is applicable to drugs or foods, drugs for animals or plants, fertilizers, feeds, and the like. In particular, it can be applied not only to orally administered drugs, but also to parenteral drugs such as inhalants and external preparations such as suppositories. Furthermore, it can be applied as a so-called quasi-drug for the purpose of disinfecting and cleaning dentures, eyeglasses, contact lenses, and the like. Example

Hereinafter, Production Examples, Test Examples, and Examples will be shown, but the invention is not limited thereto. In the following examples, "parts" means "parts by weight" and "%" means "% by weight". Comparative Example 1

9. Mix 5 parts of polyethylene glycol (PEG) 400 with 0.5 parts of purified water, and mix the mixture with the first size gelatin hard capsule (HGC), hydroxypropyl methylcellulose hard capsule (HPMC) or pullulan. Hard capsules (HPC) were filled with a commercially available disposable lml syringe in approximately 0.3 ml each to obtain hard capsules. Comparative Example 2

0.5 part of distilled water and 2.5 parts of polyvinylpyrrolidone (P VP) K25 are mixed and dissolved in 7 parts of PEG400, and the resulting solution is commercially available to the first size HGC, HPMC or HPC, respectively. The product was filled into disposable lm1 syringes in about 0.3 ml each to obtain hard capsules. Production Example 1

9 parts of vitamin E succinate polyethylene glycol 1000 ester (TPGS) melted at about 60 ° C and 1 part of PEG400 are mixed, and the resulting mixture is marketed as a 1st size HGC, HPMC or HPC. Each disposable lm1 syringe was filled in about 0.3 ml to make a hard capsule. Production Example 2

7 parts of TPGS melted at about 60 and 3 parts of PEG400 were mixed well, and the resulting mixture was added to the first size HGC, HPMC or HPC using a commercially available disposable lm 1 syringe. Each 3 ml was filled to give a hard capsule. Production Example 3

9 parts of TP GS melted at about 60 ° C and 1 part of propylene glycol (PG) are mixed well, and the obtained mixture is put into the first size HGC, HPMC or HPC, which is a commercial product. The disposable lm1 syringe was filled in approximately 0.3 ml each to make a hard capsule. Production Example 4

7 parts of TPGS melted at about 60 ° C and 3 parts of PG are mixed well, and the obtained mixture is added to the No. 1 size HGC, HPMC or HPC using a commercially available disposable 1 ml syringe. Each 3 ml was filled to obtain a hard capsule. Production Example 5

6.7 parts of TPGS melted at about 60 ° C and 3 parts of PG dissolved in 0.3 parts of PVPK25 were mixed well, and the resulting mixture was mixed with the first size HGC, 'HP MC Alternatively, about 0.3 ml of HPC was filled with a commercially available disposable lm1 syringe to prepare hard capsules. Production Example 6

9 parts of polyoxyethylene hydroxystearic acid (HS 15) melted at about 40 ° C and 1 part of PG are mixed well and mixed with No. 1 size HGC, HPMC and HPC using a commercially available disposable lml syringe. 3 ml was filled to give a hard capsule. Production Example 7

Six parts of Gelucire44 / 14, a polyethylene glycol 1500 fatty acid triglyceride melted at about 60 ° C, 3 parts of Labrasol, a polyethylene glycol 1500 fatty acid triglyceride, and 1 part of diethylene glycol ether were mixed well, and the resulting mixture was mixed. The liquid was filled into each of the first size HGC, HPMC or HPC with a commercially available disposable lml syringe in an amount of about 0.3 ml to obtain a hard capsule. Production Example 8 9 parts of Imwiter 742, a medium-chain fatty acid ester of glycerin melted at about 60 ° C, and 1 part of polyoxyethylene hydrogenated castor oil (HC〇) 60 were mixed well under about 6 Ot, and the resulting mixture was mixed. Each of the solutions was filled into a No. 1 size HGC, HPMC or HPC with a commercially available disposable lm1 syringe in an amount of about 0.3 ml each to obtain a hard capsule. Example 1

Eight parts of TPGS melted at about 60 ° C, one part of PEG400 and one part of purified water are mixed, and the resulting mixture is put into the first size HGC, HPMC or HPC, a commercially available disposable lm. Approximately 0.3 ml was filled with each syringe to give hard capsules. Example 2

Previously, 0.5 parts of PVPK25 was dissolved. Three parts of PEG400 and 0.5 part of distilled water were mixed well with 6 parts of TPGS, which was melted at about 60 ° C, and dissolved.The resulting mixture was the first size HGC, HPMC, or HPC Then, about 0.3 ml was filled with a commercially available disposable lm1 syringe into hard capsules. Example 3

8 parts of TPGS melted at about 60 ° C, 1 part of propylene glycol (PG) and 1 part of purified water are mixed well, and the resulting mixture is mixed with the first size HGC, HPMC or HPC. Then, about 0.3 ml was filled with a commercially available disposable lm1 syringe into hard capsules. Example 4

5 parts of HS 15 and 1 part of PG and 1 part of purified water and high-grade fat melted at about 40 ° C Three parts of fatty alcohol were mixed well, and the resulting mixture was filled into the first size HGC, HPMC or HPC with a commercially available disposable lm 1 syringe in an amount of about 0.3 ml each to obtain hard capsules. . Example 5

Mix well 4.5 parts of Gelucire44 / 14 melted at about 60 ° C, 2 parts of Labrasol, 0.5 parts of ethylene glycol ether, and 3 parts of glycerin palmitostearate, a long-chain fatty acid ester of glycerin. Then, the obtained mixed solution was filled into each of the first-size HGC, HPMC or HPC with a commercially available disposable lm1 syringe in an amount of about 0.3 ml to prepare a hard capsule. Example 6

8 parts of Imwiter 742, a medium-chain fatty acid ester of glycerin melted at about 60 ° C, and 1 part of polyoxyethylene hydrogenated castor oil (HC〇) 60 are mixed and dissolved well under about 60 parts. One part of Keiic acid was added and mixed well. The obtained mixture was filled into each of the first size HGC, HPMC or HPC with a commercially available disposable lml syringe in an amount of about 0.3 ml to prepare a hard capsule. Test example 1: Appearance change test

Production Examples 1 to 8 are placed in a test tube with the body part down so that the internal solution does not leak from the joint between the cap and the body, and the opening of the test tube is sealed. They were stored for 6 months in a constant temperature room at 40 ° C, an accelerated test condition equivalent to one year, and changes in appearance (dissolution, cracking, leakage, deformation, etc.) were observed. The results are shown in the table below. In the table, 〇 indicates that there is no change in appearance, and X indicates that softening, cracking, leakage, and deformation occur. Table 1

As shown in the table above, the HGC capsules of Comparative Example 1, Production Examples 4 and 5, and the HPMC capsules of Comparative Examples 1, 2, and Production Examples 1 to 5 and 7, which do not contain a quality preservative, are softened. , Cracks and deformations, indicating nonconformity. On the other hand, Examples 1-6 containing a quality preservative show compliance. Test example 2: Dissolution test

For HGC or HPMC capsules of Comparative Example 2, Production Examples 1, 2, 3, 6, 7, and 8 in which there was no significant change in the appearance during the storage period in Test Example 1, the filled liquid was removed, and the Instead, about 25 Omg of acetoaminophen was filled to obtain acetoaminophen capsules. According to the second method of the dissolution test of the 14th revision of the Japanese Pharmacopoeia, the dissolution rate of acetoaminophen from the acetominophen forcepsel was measured at 50 paddle rotations using purified water as the eluate. The results are shown in the table below. The values in the table indicate the dissolution rate of acetaminophen after 45 minutes (%) Is shown. Also, X indicates that the dissolution rate of acetaminophen after 45 minutes was 85% or less, which was an unsatisfactory result. The dissolution rate is an average of two tests.

As shown in the above table, there was no significant change in appearance.Comparative Example 2 containing no quality preservative and Production Examples 1, 2, 3, 6, 7, and 8 from acetates from HGC or HPMC capsules. The dissolution rate of minofen after 45 minutes is less than 85%, which is significantly lower than that of capsules (non-preserved products) that have not been stored under the conditions described above. This indicates that various hydrophilic solubilizers had an adverse effect. This is due to the fact that gelatin, which is the main component of HGC, was altered by various hydrophilic solubilizers, and gelatin was insolubilized accordingly, and HPMC was gelled. It was considered. On the other hand, the dissolution rate from the three kinds of capsules of Examples 1 to 6 containing the quality preservative was the same as that of the non-preserved product, and the dissolution rate of acetaminophen after 45 minutes was 85% or more. This shows that there was no adverse effect of various hydrophilic solubilizers on quality. Toes In addition, it was found that purified water, PVP, higher fatty alcohol, glycerin medium-chain fatty acid ester, and light acid anhydride were effective as a quality preservative for forcepsell materials. Example 7

Using the same hydrophilic solubilizing agent composition as in Example 1, 81 capsules were prepared as follows. That is, danazol was dissolved by mixing lg (10% by weight) of danazol, 7 g of TPGS, 0.7 g of PEG and 0.6 g of sodium lauryl sulfate under heating at about 80 ° C. . After dissolution, add 0.7 g of purified water and mix well.Fill this solution with 0.3 g of HGC, HPM C or HP C capsule of No. 1 size using a commercially available disposable lm 1 syringe. A danazol capsule containing about 30 mg per capsule was prepared. Example 8

Hard capsules were prepared with the same hydrophilic solubilizer composition as in Example 2 as follows. In other words, 0.05 g of polyvinylpyrrolidone K25 was previously mixed well with 0.3 g of PEG400 and 0.05 g of purified water while heating at about 80 ° C., and dissolved. 0.7 g of TPGS was added to this mixed solution, mixed well and dissolved. To the obtained mixture, 0.2 g (15.4% by weight) of cyclosporine was added, mixed well at about 80 ° C. and dissolved. This drug solution was filled into HPMC or HPC capsules of No. 1 size by about 0.3 ml each using a commercially available disposable lml syringe to prepare cyclosporine capsules containing about 45 mg per capsule. Example 9

Hard capsules were prepared with the same hydrophilic solubilizing agent composition as in Example 3 as follows. That is, evening crolimus 0.2 g (10% by weight) and TPGS 1.4 g And PG were mixed well with 0.2 g under heating at about 80 ° C to dissolve chlorimus in the evening. After dissolution, add 0.05 g of purified water and mix well.Fill this solution with a commercially available disposable lm l syringe into each No. 1 size HGC or HPC capsule in approximately 0.3 m1. A tact-mouth limus capsule containing about 30 mg per capsule was prepared. Example 10

Hard capsules were prepared with the same hydrophilic solubilizer composition as in Example 4 as follows. That is, 2 g (17% by weight) of probucol, 7 g of HS 15, 1 g of PG, and cetostearyl alcohol were mixed well under heating at about 80 ° C to dissolve probucol. After dissolution, add 0.5 g of purified water and mix well.Fill this solution with a commercially available disposable lm 1 syringe into each No. 1 size HGC or HPC capsule in approx.0.3 ml each, 1 capsule A probucol capsule containing about 5 Omg per was prepared. Example 11

Hard capsules were prepared with the same hydrophilic solubilizing agent composition as in Example 5 as follows. In other words, 0.3 g (10% by weight) of evening moxifen, 1.4 g of Gelucire44 / 14 melted at 60 ° C, 0.6 g of Labrasol, and 0.2 g of dimethylene glycol were dissolved. g and 0.5 g of glycerin palmitostearate, a long-chain fatty acid ester of glycerin, were mixed well at about 60 and dissolved. After dissolution, add 0.05 g of purified water and mix well.Fill this drug solution with a commercially available disposable lm 1 syringe into each of the first size HGC or HPC capsules in approx. An evening moxifen capsule containing about 3 Omg per day was prepared. Example 1 2 Using the same hydrophilic solubilizing agent composition as in Example 6, 81 capsules were prepared as follows. In other words, 15 g of Imwiter 742 melted at about 60 ° C and 2 g of polyoxyethylene hydrogenated castor oil (HCO) 60 are mixed well under about 60, and 1 g of albendazole (5 wt% ) Was added and dissolved. In addition, 1 part of light anhydrous silicic acid was added and mixed well. Fill the obtained mixture with each of the No. 1 size HGC, HPMC, or HPC using a commercially available disposable lm 1 syringe with about 0.3 ml each to prepare an albendazole capsule containing about 15 mg per capsule. did. Example 13

Eighteen capsules were prepared with the same hydrophilic solubilizer composition as in Example 1 as follows. In other words, 7.13 g of TPGS dissolved in 2.5 g (22% by weight) of albendazole at about 60 ° C, lg of PEG400, and 0.87 g of 12N hydrochloric acid aqueous solution at about 60 ° C Mix well with C and dissolve. The obtained liquid mixture was filled into HGC, HPMC or HPC of No. 1 size by about 0.3 ml each with a commercially available disposable lml syringe to prepare an albendazole capsule containing about 66 mg per capsule. Example 14

With the same hydrophilic solubilizing agent composition as in Example 4, a hard capsule was prepared as follows. In other words, 3 g (25% by weight) of domperidone and 7.35 g of HS 15 melted at about 40 ° C, 1 g of PG, and 0.65 g of 12N hydrochloric acid aqueous solution at about 60 ° C Mix well and dissolve the obtained mixture into each of the 1st size HGC, HPMC or HPC with a commercially available disposable 1 m 1 syringe, filling about 0.3 ml each, and a capsule containing about 75 nag per capsule. Don capsules were prepared. Example 15

Eighteen capsules were prepared with the same hydrophilic solubilizer composition as in Example 4 as follows. In other words, 4 g (29% by weight) of Todari Yuzon and 7.2 g of HS 15 melted at about 40 ° C, 1 g of PG, and 1.8 g of 4N potassium hydroxide aqueous solution were added to about 60 g. Mix well at ° C and dissolve.The resulting mixture is filled into each No. 1 size HGC, HPMC or HPC with a commercially available disposable lm 1 syringe in about 0.31 ml each, containing about 9 Omg per capsule A todary evening capsule was prepared. Example 16

Using the same hydrophilic solubilizing agent composition as in Example 1, 81 capsules were prepared as follows. That is, 3.5 g (25% by weight) of pranlukast, 8 g of TPGS melted at about 60 ° C, 1 g of PEG400, and 1.5 g of 4N aqueous sodium hydroxide solution at about 60 ° C Mix well with C. The resulting mixture is filled into each No. 1 size HG C, HPMC or HPC using a commercially available disposable lml syringe in an amount of about 0.3 ml, and pranluca containing about 75 mg per capsule A strike capsule was prepared. Example 17

5 g (50% by weight) of ibuprofen, 3 g of HS 15 and 1 g of PG are mixed well, and then 1 g of 12N aqueous sodium hydroxide solution is added. Dissolved. The resulting mixed solution was filled into the first size HGC, HPMC, and HPC with a commercially available disposable lm 1 syringe in an amount of 0.3 ml to prepare an ibuprofen capsule containing about 15 Omg per capsule.

The capsule fillings of Examples 7 to 17 were all prepared using artificial gastric juice (pH 1.2) and artificial intestinal juice (pH 6. 8), and the poorly water-soluble drug did not precipitate in the solution for 2 hours. It can be seen that the absorption of the poorly water-soluble drug into the living body is improved. Industrial applicability

The hard capsule of the present invention may contain a hydrophilic solubilizing agent for improving the solubility of a poorly water-soluble drug in water, for example, the appearance change such as softening, dissolution, leakage, cracking and deformation, or the drug Substantially no qualitative change such as deterioration of the dissolution property of the compound is observed. When the hard capsule of the present invention is used as a drug for oral administration, the solubility of the poorly water-soluble drug in water is improved by the hydrophilic solubilizing agent, so that the oral absorption of the filled poorly water-soluble drug is improved. There is an advantage that it can be improved. Furthermore, unlike the conventional soft force presser, the hard force presser of the present invention does not substantially limit the viscosity of the contents, and can also fill contents having a relatively high viscosity. Further, the hard capsule preparation of the present invention is hardly affected by the humidity and temperature of the environment, and is easy to distribute and handle.

Claims

The scope of the claims

1. A hard capsule containing a poorly water-soluble drug, (i) a surfactant or (ii) a hydrophilic solubilizer containing a hydrophilic solvent and a surfactant, and a quality preservative. A hard capsule of a poorly water-soluble drug, characterized in that the capsule is filled with water.

2. The quality preservatives are: (a) purified water, (b) a thickener that makes the kinematic viscosity of the content 100 to 2000 (mpas), and (c) a high melting point that makes the melting point of the content 30 to 80 ° C The hard capsule preparation according to claim 1, which is any one of additives having a melting point or a combination thereof.

3. The quality preservative is (a) purified water, (b) cellulose-based polymer or polyvinylpyrrolidone, or a solution obtained by dissolving and dispersing the above substance in purified water or polyhydric alcohol or a mixture thereof, (c) light 2. The hard capsule preparation according to claim 1, wherein the preparation is at least one selected from the group consisting of a silicic anhydride, (d) a higher fatty alcohol, and (e) a glycerin long-chain fatty acid ester.

4. The hard capsule preparation according to any one of claims 1 to 3, wherein the content filled in the hard capsule is semi-solid or liquid.

5. The hard capsule according to any one of claims 1 to 4, wherein the hardly water-soluble drug is contained in an amount of 0.1 to 50% by weight.

6. The first claim, wherein the hydrophilic solubilizer is contained in an amount of 20 to 99.8% by weight. Item 6. The hard capsule according to any one of Items 5 to 5.

7. The hard capsule according to any one of claims 1 to 6, wherein the quality preservative is contained in an amount of 0.1 to 30% by weight.

8. The hard capsule preparation according to any one of claims 1 to 7, wherein the surfactant contains at least vitamin E succinate polyethylene ester or polyoxyethylene hydroxy fatty acid ester.