WO2016017006A1 - カプセル製剤 - Google Patents
カプセル製剤 Download PDFInfo
- Publication number
- WO2016017006A1 WO2016017006A1 PCT/JP2014/070242 JP2014070242W WO2016017006A1 WO 2016017006 A1 WO2016017006 A1 WO 2016017006A1 JP 2014070242 W JP2014070242 W JP 2014070242W WO 2016017006 A1 WO2016017006 A1 WO 2016017006A1
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- WO
- WIPO (PCT)
- Prior art keywords
- oil
- capsule
- formulation
- active ingredient
- acid
- Prior art date
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- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
- B65B7/00—Closing containers or receptacles after filling
- B65B7/16—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons
- B65B7/28—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons by applying separate preformed closures, e.g. lids, covers
- B65B7/2842—Securing closures on containers
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- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D65/00—Wrappers or flexible covers; Packaging materials of special type or form
- B65D65/38—Packaging materials of special type or form
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- B65D65/463—Edible packaging materials
Definitions
- the present invention relates to a capsule preparation.
- DRcaps (trademark) manufactured by Capsugel is a hard capsule in which the capsule film is hydrophilic and acid resistant.
- the formulation can be acidified only by being enclosed in the capsule (Patent Document 1).
- Such acid-resistant capsules are useful for intestinal delivery because they do not dissolve when placed in an acidic solution and the hard capsules do not disintegrate in the stomach in vivo. Therefore, when encapsulating an active ingredient or the like that is sufficient if the hard capsule does not disintegrate in the stomach (for example, garlic that is concerned about the return odor) in the hard capsule, the expected effect is obtained and there is no particular problem. .
- the present inventors surprisingly, even if the capsule does not disintegrate in the stomach, the capsule film contains a hydrophilic material. Therefore, it was found that gastric acid gradually infiltrates through the capsule film over time. And even if the capsule film itself uses a capsule having acid resistance, when an active ingredient whose efficacy is reduced by a small amount of gastric acid (gastric juice) is encapsulated, the acid (gastric acid) touches the active ingredient. As a result, the active ingredient is deteriorated (changed / decomposed / died), and the expected effect may not be sufficiently obtained.
- gastric acid gastric acid
- the present invention provides an active ingredient from gastric acid that permeates into the capsule film without necessarily requiring an enteric coating in a capsule preparation containing an active ingredient that can deteriorate when exposed to acid. It aims to provide a means to protect.
- the present invention includes the following embodiments.
- a capsule preparation containing an active ingredient and oil wherein the capsule of the preparation is an enteric capsule containing a water-soluble film-forming polymer and gellan gum, and the oil is pharmaceutically or edible. It is oil, The said active ingredient is enclosed with the said oil with the said capsule,
- the capsule formulation characterized by the above-mentioned.
- a method for producing a capsule preparation containing an active ingredient and oil wherein the capsule of the preparation is an enteric capsule containing a water-soluble film-forming polymer and gellan gum, The method includes the following steps: dispersing the active ingredient in the oil, and encapsulating the oil in which the active ingredient is dispersed in the capsule.
- a process for producing a capsule formulation characterized in that
- a method for producing the capsule preparation according to (12), wherein the capsule is a hard capsule having a body part and a cap part, and after the step of encapsulating in the capsule, the body part and the cap part A method for producing a capsule preparation, further comprising a step of sealing the fitting portion with a band seal.
- the capsule preparation according to the present invention protects an active ingredient that can deteriorate (eg, change / degrade / kill) when exposed to acid from the acid (gastric acid) that permeates into the capsule. be able to. That is, oil has the property of not separating and mixing even when mixed with an acid (gastric acid), so that the acid (gastric acid) infiltrated into the capsule is pharmaceutically or foodically encapsulated in the capsule. Without diffusing into acceptable oil, it sinks to the bottom of the capsule due to the specific gravity difference with oil. Therefore, the contact between the acid and the active ingredient can be effectively reduced by separating the aqueous phase (containing the acid) and the oil phase (containing the active ingredient) inside the capsule.
- oil has the property of not separating and mixing even when mixed with an acid (gastric acid), so that the acid (gastric acid) infiltrated into the capsule is pharmaceutically or foodically encapsulated in the capsule. Without diffusing into acceptable oil, it sinks to the bottom of the capsule due to the specific gravity difference with
- the capsule formulation which concerns on this invention employ
- the capsule preparation according to the present invention can easily maintain a delicate balance between protection from gastric acid and rapid disintegration in the intestine (such as the small intestine or large intestine), and does not require an advanced formulation design. This is advantageous.
- FIG. 1 is a photograph showing the capsule preparation produced in Example 1 (photo left: MCT (present invention); photo right: glycerin (comparative example)).
- the litmus reagent was uniformly dispersed in the MCT solution (the capsule liquid color was light blue), but dissolved in the glycerin solution (the capsule liquid color was dark blue).
- FIG. 3 is a photograph before the capsule preparation prepared in Example 2 is submerged in the first solution of Japanese Pharmacopoeia (pH 1.2 solution) maintained at 37 ° C. (from the bottom of the photograph, in order, glycerin fatty acid ester, Sorbitan fatty acid ester, safflower oil, olive oil, soybean oil, linseed oil, DHA, rice germ oil, vitamin E, vitamin A).
- FIG. 1 Japanese Pharmacopoeia
- FIG. 5 is a photograph of the vicinity of the capsule formulation fitting part 120 minutes after submerging in the first solution of Japanese Pharmacopoeia (pH 1.2 solution) maintained at 37 ° C when using DHA and vitamin E, respectively.
- the photograph taken and the enlarged photograph thereof are shown (upper left photo: DHA, lower left photo: enlarged photo when using DHA, upper right photo: vitamin E, lower right photo: enlarged photo when using vitamin E).
- the present invention relates to a capsule preparation containing an active ingredient and oil (hereinafter also referred to as a capsule preparation according to the present invention).
- the capsule is an enteric capsule containing a water-soluble film-forming polymer and gellan gum, the oil is a pharmaceutically or edible oil, and the active ingredient is the It is characterized by being enclosed in the capsule together with oil.
- the capsule preparation of the present invention may be used for any purpose as long as it is suitable, but is preferably used as a capsule for medical use or health food.
- the capsule may be any capsule such as a soft capsule and a hard capsule as long as it can form a film capable of enclosing the contents according to the present invention (that is, containing an active ingredient and oil).
- the term “enteric” means that the capsule does not substantially dissolve (disintegrate) by gastric acid or in the stomach, but dissolves in the intestine (small intestine, large intestine). Used interchangeably with the term “acid resistant”.
- any water-soluble film-forming polymer that can be used as a base material for capsules can be used as the water-soluble film-forming polymer.
- Such water-soluble film-forming polymers include, but are not limited to, for example, cellulose derivatives, preferably hydroxypropyl methylcellulose (HPMC), gelatin, pullulan, polyvinyl alcohol (PVA) and starch derivatives, preferably Can be selected from the group consisting of hydroxypropyl starch.
- the water-soluble film-forming polymer forms an elastic module and a film with optimal mechanical performance in terms of brittleness, so that it consists of HPMC, gelatin, pullulan, PVA and hydroxypropyl starch More selected.
- the water-soluble film-forming polymer may be a single type or a combination of multiple types.
- the film-forming polymer comprises HPMC and / or gelatin.
- the film-forming polymer consists of HPMC.
- the film-forming polymer consists of gelatin.
- Gellan gum is an exopolysaccharide produced by fermentation.
- the ratio of gellan gum to the water-soluble film-forming polymer is not particularly limited as long as it is a ratio capable of imparting acid resistance to the capsule, and those skilled in the art will depend on the type of water-soluble film-forming polymer used. An appropriate ratio can be determined as appropriate.
- the gellan gum is about 4-15 parts by weight, preferably about 4.5-8 parts by weight, more preferably about 4.5 parts by weight with respect to 100 parts by weight of the water-soluble film-forming polymer. It can be used at a ratio of ⁇ 6 parts by mass.
- gellan gum is used in a ratio of about 5 or 5.5 parts by weight per 100 parts by weight of the water-soluble film-forming polymer.
- an amount of gellan gum less than the lower limit shown above is used, there is a possibility that the final capsule cannot be provided with sufficient acid resistance against digestive fluid such as stomach acid.
- gellan gum is used in an amount greater than the upper limit shown above, it can result in excessive viscosity and excessive gelling, which can make it difficult to produce high quality capsules.
- the capsule of the present invention can be produced by a method well known to those skilled in the art.
- a gel pin is dipped in an aqueous composition in which a water-soluble film-forming polymer and gellan gum are dissolved, pulled up, and dried to dry the aqueous composition attached to the immersion pin.
- a hard capsule can be manufactured by the method of obtaining.
- Plasticizers, preservatives, dispersants (dextrin, sucrose, mannitol, maltose, etc.), colorants, lubricants, disintegrants, surfactants and other additives are known for better capsule production However, these can also be used as appropriate in the capsule of the present invention.
- a commercially available capsule may be used.
- DRcaps trademark which is a hard capsule manufactured by Capsugel.
- the present invention does not necessarily exclude capsules having an enteric coating on the capsule film. Therefore, the capsule may have an enteric coating on the capsule film. However, in order to effectively obtain the advantages of the present invention, an enteric coating need not be applied.
- the capsule used in the present invention is a hard capsule having a body part and a cap part covering the body part
- the body part and the cap constituting the capsule body are preferably used to prevent leakage of the contents.
- the fitting part (seam) with the part is sealed with a band seal.
- the preparation and sealing method of the band seal solution used for the band seal may be appropriately performed based on means and methods known to those skilled in the art.
- the band seal liquid the same composition as the hard capsule coating liquid (aqueous composition) may be used.
- International application PCT / US2013 / 041838 filing date: May 20, 2013 based on unpublished US patent application No.
- the band seal liquid used for the band seal in the present invention the band seal liquid disclosed in this US application may be used.
- the composition after drying of the solution is alcohol: about 0 mass%, ammonia water: about 0 to 10% by mass, shellac: about 20 to about 100% by mass, rosin: about 0 to 35% by mass, surfactant: 0 to 10% by mass, dye: about 0 to 70% by mass, glycerin, triacetin, polyoxyethylene glycol Derivatives, plasticizers such as polyethylene glycol and phthalates: 0 to 15% by mass, fluidizing agents such as hydrous silicon dioxide, starch, crystalline cellulose and talc: 0 to 50% by mass.
- an active ingredient in this specification, sometimes referred to as an active ingredient or the like
- turmeric extract e.g, turmeric extract, ginseng extract, plum extract, ginkgo leaf
- the physiologically active substance itself may be pointed out, or it does not exhibit biological activity itself but deteriorates upon contact with an acid, so that the physiologically active substance enters the intestine. It may refer to a substance that can affect delivery.
- the active ingredient preferably has a strong lipophilic tendency and / or a strong hydrophobic tendency.
- the active ingredient is more preferable if the ingredient deteriorates (eg, changes / decomposes / destroys) when exposed to acid (gastric acid), for example, the quality or titer is reduced. .
- the amount of active ingredient relative to the entire contents encapsulated is expected under the given conditions (active ingredients, etc., excipients, pharmaceutically or food acceptable oils, capsules, their capacity, etc.) It can be included in such an amount that it can exert the effect to the extent of.
- the “pharmaceutically or food-acceptable oil” in the present invention (in the present specification, sometimes simply referred to as “oil”) is encapsulated in a capsule so that the capsule preparation is used. Reduces or substantially (completely) acid (acid solution, for example, gastric juice in vivo) from penetrating into the capsule through the capsule membrane and coming into contact with the inclusions (especially active ingredients) in the capsule Or partially)). That is, although the oil is not limited, it exhibits a hydrophobicity with respect to the aqueous phase (including gastric acid which is an acidic solution), so that it exists separately without mixing with the aqueous phase to form an oil phase. There is no particular limitation as long as it can.
- the oil in the present invention may be liquid (fatty oil or the like) or solid (fatty or the like) at room temperature.
- the oil in the present invention is preferably a liquid at an in vivo temperature (particularly, the temperature of the stomach, around 37 ° C.).
- fat contains many saturated fatty acids (eg, palmitic acid, stearic acid), while fatty oils contain many unsaturated fatty acids (eg, oleic acid, linoleic acid, linolenic acid). These may be esterified. It is known that the higher the degree of unsaturation of an oil, the lower the melting point, and it tends to become liquid at a low temperature (easily oxidized).
- oils in the present invention include medium chain fatty acids (for example, medium chain fatty acid triglycerides such as tri (caprylic acid / capric acid) glycerin and glyceryl tricaprylate) and long oils. Chain fatty acids are preferred.
- the oil in the present invention may not be a fatty acid, and includes, for example, a fat-soluble (oil-soluble) substance.
- fat-soluble vitamins such as vitamin A (oil), vitamin D (oil), vitamin E (oil), vitamin K (oil), and derivatives thereof, and glycerophospholipids such as lecithin are also included in the oil of the present invention. included.
- lecithin that can be used in the present invention for example, lecithin obtainable from plants such as soybean, rice, rapeseed, safflower, lecithin obtainable from animals such as egg yolk, these lecithins are chemically or The lecithin derivative obtained by carrying out an enzyme process can be mentioned.
- lecithin derivatives include enzymatically decomposed lecithin, hydrogenated enzymatically decomposed lecithin, hydroxy lecithin, phosphatidylglycerol, phosphatidic acid, acetylated lecithin and the like.
- the oil in the present invention is preferably vegetable oil, animal oil, fish oil or mineral oil, and edible oil is preferred from the viewpoint of being pharmaceutically or food acceptable. In one embodiment, vegetable oil is further preferred.
- Coriander oil Dika oil, Amana oil, Grapes Deoil, hemp oil, kapok seed oil, llare manthia oil, marula oil, meadow foam oil, mustard oil, okra oil (hibiscus oil), papaya oil, egoma oil (seed oil), poppy oil, prune oil, quinoa oil , Niger seed oil, camellia oil (camellia oil), thistle oil, tomato oil, krill oil (krill oil), borage oil, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), but are not limited thereto.
- DHA docosahexaenoic acid
- EPA eicosapentaenoic acid
- the oil in the present invention preferably has a specific gravity (density ratio based on water) of 0.96 or less, more preferably 0.955 or less, and 0.95 or less. More preferably, it is more preferably 0.945 or less, and still more preferably 0.94 or less.
- the amount of oil relative to the entire contents enclosed in the capsule can exert the expected effect under given conditions (active ingredients, excipients, capsules, their volume, etc.). Can be included in quantity.
- the amount of such oil relative to the entire contents enclosed in the capsule is preferably such that, for example, the active ingredient contained in the capsule is sufficiently soaked in the oil. More preferably, it is dispersed or dissolved.
- the amount of such oil is, for example, 30% by mass or more, 35% by mass or more, 40% by mass or more, or 40 to 99.9% by mass with respect to the entire contents enclosed in the capsule. it can.
- a person skilled in the art can appropriately determine an appropriate amount according to the active ingredient and the type of oil, but in general, the larger the amount of oil enclosed in the capsule, the better.
- a food-acceptable surfactant may be included.
- surfactants include, but are not limited to, monoglycerol fatty acid esters, diglycerol fatty acid esters, polyglycerol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, propylene glycol fatty acid esters, or any of these A combination etc. are mentioned.
- the amount of such a surfactant with respect to the entire contents encapsulated in the capsule is, for example, preferably 5% by mass or less, more preferably 3% by mass or less, and more preferably 1% by mass. Even more preferably: Further, since the surfactant has amphiphilic properties, it is preferable that the HLB value (a value representing the degree of affinity of the surfactant with water and oil) is low, that is, hydrophobic. And / or a thing with a strong tendency of lipophilicity is preferable.
- a surfactant having an HLB value of about 3 to 6 is relatively preferable because it partially disperses in the aqueous phase, and a surfactant having an HLB value of about 1 to 3 is more preferable because it hardly disperses in the aqueous phase. Those skilled in the art can appropriately determine and optimize the appropriate amount of the surfactant in consideration of these common technical knowledge.
- the capsule preparation of the present invention may be produced by a method comprising the steps of encapsulating an active ingredient in the capsule of the present invention; and encapsulating a pharmaceutically or food acceptable oil in the capsule. These two steps may be performed simultaneously or separately. When the two steps are performed simultaneously, the step of dispersing or dissolving the active ingredient in a pharmaceutically or food-acceptable oil; and the step of encapsulating the oil in which the active ingredient is dispersed or dissolved in the capsule You may do it at the same time.
- the capsule preparation of the present invention comprises a step of mixing an active ingredient and a surfactant in a pharmaceutically or food acceptable oil and emulsifying the active ingredient in the oil; And you may manufacture by the method including the process of enclosing the oil in which the said active ingredient was emulsified in the said capsule, and these two methods may be performed simultaneously or may be performed separately.
- the oil in the present invention is a solid at room temperature, for example, the capsule preparation is produced while warming the oil to a liquid in anticipation of the dissolution or dispersion of the active ingredient (and optionally a surfactant) in the oil. You may use for.
- the capsule preparation of the present invention is administered by a method according to the type of the active ingredient, the age of the subject, sex, disease state, and other conditions.
- the dosage of the capsule preparation of the present invention may be appropriately selected according to the usage, age of subject, sex, degree of disease, and other conditions.
- the frequency of administration may be appropriately selected according to the usage, age of the subject, sex, degree of disease, and other conditions. For example, 3 times / 1 day, 2 times / 1 day, 1 time / 1 day, Depending on the blood stability, a less frequent administration frequency (for example, once / week, once / month, etc.) may be selected.
- any numerical value used to indicate the component content or numerical range is interpreted as including the meaning of the term “about” unless otherwise specified.
- “10 times” is understood to mean “about 10 times” unless otherwise specified.
- MCT medium chain fatty acid triglyceride, Coconut MT (Kao Co., Ltd.)
- glycerin manufactured by Kao Corporation
- DRcaps Capsugel acid-resistant hard capsules
- the band seal liquid is an unpublished international application PCT / US2013 / 041838 (application) based on US Patent Application No. 61 / 707,135 (filing date: September 28, 2012). (May 20, 2013) (name of invention "ACID RESISTANT BANDING SOLUTION FOR TWO PIECE HARD CAPSULES").
- the composition of the band seal solution was ethanol: 59.9% by mass, shellac: 37.0% by mass, water 1.6% by mass, and surfactants (sorbitan fatty acid ester and glycerin fatty acid ester) 1.5% by mass. .
- Example 2 Experiments were conducted in the same manner as the conditions used in Example 1 (amount of oil, measurement conditions, measurement time, etc.) to examine the effect on acid resistance when other oils or surfactants were encapsulated. In this example, the determination was made based on the following criteria based on the color of the fine litmus powder dissolved or dispersed in the oil enclosed in the capsule. “-”: Almost all red / unsuitable “+”: Half of red / possible “++”: All blue / excellent.
- the present inventors surprisingly relate to the degree of unsaturation as a measure of stability.
- various oils in the present invention show acid resistance.
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Abstract
Description
上記の問題点を鑑み、本発明は、酸に触れると成分が劣化し得る有効成分等を含むカプセル製剤において、必ずしも腸溶性コーティングを要することなく、カプセル皮膜に滲み込んでくる胃酸から有効成分を保護する手段を提供することを目的とする。
以上、(1)~(14)で述べた本発明の一又は複数の特徴を、当業者の観点から技術的に矛盾しないように任意に組み合わせたものも、本発明の範囲に含まれることはいうまでもない。
また、本発明に係るカプセル製剤は、別の態様において、医薬的または食品的に許容できる油に分散された有効成分がカプセルに封入されている、という非常に簡便な構成を採用する。これにより、本発明に係るカプセル製剤は、胃酸からの保護と腸(小腸または大腸など)内での速やかな崩壊との巧妙なバランスを容易に保つことができ、高度な処方設計を必要としない点で有利である。
本発明において、用語「腸溶性」とは、胃酸によってまたは胃中ではカプセルが実質的に溶解しない(崩壊しない)が、腸(小腸、大腸)で溶解することを意味し、本明細書中、用語「耐酸性」と交換可能に使用される。
本発明における油としては、常温で、液体(脂肪油等)であってもよいし、固体(脂肪等)であってもよい。本発明における油は、一実施態様において、生体内の温度(特に、胃の温度、37℃前後)において液体であるのが好ましい。一般に、脂肪には多くの飽和脂肪酸(例えば、パルミチン酸、ステアリン酸)が含まれる一方で、脂肪油には多くの不飽和脂肪酸(例えば、オレイン酸、リノール酸、リノレン酸)が含まれる。これらはエステル化されていてもよい。油の不飽和度が高いほど融点が下がり、低温で液体となりやすい(酸化されやすい)ことが知られているが、本発明者は、驚くべきことに、不飽和度に関係なく、多様な油が本発明における油として有用であることを見出した。
一般に、炭素数2~4個の脂肪酸を短鎖脂肪酸(低級脂肪酸)、5~12個の脂肪酸を中鎖脂肪酸、12個以上の炭素数の脂肪酸を長鎖脂肪酸(高級脂肪酸)と呼ぶ。一般に脂肪酸は炭素数が少ないと親水性が高まることから、本発明における油としては、中鎖脂肪酸(例えば中鎖脂肪酸トリグリセリド、例えば、トリ(カプリル酸・カプリン酸)グリセリンやトリカプリル酸グリセリル)及び長鎖脂肪酸が好ましい。
また、本発明における油としては、脂肪酸でなくてもよく、例えば、脂溶性(油溶性)物質も含まれる。例えば、ビタミンA(油)、ビタミンD(油)、ビタミンE(油)、ビタミンK(油)、及びこれらの誘導体のような脂溶性ビタミンや、レシチンのようなグリセロリン脂質も本発明における油に含まれる。なお、本発明に使用し得るレシチンとしては、例えば、ダイズ、コメ、ナタネ、サフラワー等の植物より得ることのできるレシチン、卵黄等の動物より得ることのできるレシチン、これらのレシチンを化学的または酵素処理することにより得られるレシチン誘導体を挙げることができる。なお、レシチン誘導体としては、例えば、酵素分解レシチン、水素添加酵素分解レシチン、ヒドロキシレシチン、ホスファチジルグリセロール、ホスファチジン酸、アセチル化レシチン等を挙げることができる。
本発明における油としては、植物油、動物油、魚油または鉱物油であることが好ましく、医薬的または食品的に許容できるという観点から、食用油が好ましい。一態様において、さらに、植物油が好ましい。ベニバナ油(サフラワー油)、オリーブ油、大豆油、アマニ油、米胚芽油、小麦胚芽油、ココナッツ油、コーン油、綿実油、パーム油、パーム核油、ピーナッツ油、菜種油、ごま油、ヒマワリ油、アーモンド油、カシュー油、ヘーゼルナッツ油、マカダミアナッツ油、モンゴンゴ油、ペカン油、松の実油、ピスタチオ油、クルミ油、ヒョウタン実油、バッファローカボチャ油、カボチャ実油、スイカ実油、アサイーベリーエキス、カシスオイル、ルリジサ種子油、月見草油、アマランサスオイル、あんず油、リンゴ油、アルガンオイル、アーティチョーク油、アボガド油、ババスオイル、モリンガ油、ケープ栗油、キャロブオイル、ヤシ油(コフネヤシ油、ノコギリヤシ油等を含む)、コリアンダー油、ディカ油、アマナズナ油、グレープシードオイル、ヘンプ・オイル、カポック実油、ラッレマンチアオイル、マルーラ油、メドウフォーム油、カラシ油、オクラ油(ハイビスカス油)、パパイヤ油、エゴマ油(シソ油)、ケシ油、プルーン油、キヌア油、ニガー種子油、ツバキ油(カメリア油)、アザミ油、トマト油、クリル油(オキアミ油)、ボラージ油、ドコサヘキサエン酸(DHA)、エイコサペンタエン酸(EPA)が挙げられるが、これらに限定されない。
酸に反応して赤色に変わるリトマス試薬(青色、和光純薬工業株式会社製造 特級)の微粉末を、有効成分として用いて、食用油であるMCT(中鎖脂肪酸トリグリセリド、ココナードMT(花王株式会社製))と水系の食用添加物であるグリセリン(花王株式会社製)(水に非常に溶けやすい、比較例)にそれぞれ0.2重量%を分散または溶解させた。ついで、これらの溶液を、カプスゲル社製耐酸性ハードカプセル(DRcaps(商標)、サイズ2号、無色透明)の分離したボディ部にそれぞれ300μL充填した。その後、当該ハードカプセルのボディ部とキャップ部の嵌合部をバンドシール液でシールしてカプセル製剤を作製した(図1を参照)。なお、バンドシール液は、未公開出願である、米国特許出願第61/707,135号(出願日:2012年9月28日)を基礎出願とする、国際出願PCT/US2013/041838号(出願日2013年5月20日)(発明の名称「ACID RESISTANT BANDING SOLUTION FOR TWO PIECE HARD CAPSULES」)に記載の情報を元に作製した。バンドシール液の組成は、エタノール:59.9質量%、シェラック:37.0質量%、水1.6質量%、界面活性剤(ソルビタン脂肪酸エルテルおよびグリセリン脂肪酸エステル)1.5質量%であった。
一方、本発明の実施例の油(MCT)を用いた製剤では、20分後、カプセル内部の底が僅かに赤くなったが、カプセル内部の大部分の液色は、酸に沈める前と変化がなかった。これは、カプセル内部に滲入した酸が、油との比重差でカプセルの底に僅かに溜まったが、油相(MCT)と水相(滲入した酸液)の2つが混じり合うことなく分離された結果、油に分散したリトマス試薬と酸液とが隔絶されていたことを意味する。さらに、カプセル内部に滲入する酸の量は、120分後もほとんど増えておらず、油に分散したリトマス試薬の、酸からの隔離が長時間維持できたことが確認できた。
実施例1で用いた条件(油の量、測定条件、測定時間等)と同様に実験を行って、他の油または界面活性剤をカプセルに封入した場合の耐酸性に関する効果を調べた。本実施例では、カプセルに封入された油に溶解または分散したリトマス微粉末の色に基づいて、以下の基準で判定した。
「-」:ほとんど全てが赤色/不適
「+」:半分程度が赤色/可
「++」:すべてが青色/優良
以下にその結果を示す。
この結果、油の代わりに界面活性剤であるグリセリン脂肪酸エステル、ソルビタン脂肪酸エステルを用いた場合には、グリセリンを用いた場合と同様に、カプセル内部全体が赤くなり、カプセル内部に滲入した酸が、カプセル内部の液全体に拡散して酸性化した。このことは、両親水性を有する界面活性剤を多量に用いた場合には、水相(酸)との親水性作用により両者が混和して、界面活性剤中に含まれる有効成分が酸に曝され得ることを示している。
一方、ドコサヘキサエン酸(DHA)を用いた場合には、カプセル内部の一部が酸性化した。しかし、ベニバナ油、オリーブ油、大豆油、アマニ油、米胚芽油、ビタミンE、ビタミンAを用いた場合については、酸と混和することはなく、カプセル内部は酸性にはなっていなかった。重要なことに、「++」の結果が得られた油は、すべて、比重が約0.94以下であった。このことは、比重が水から離れる油ほど、カプセル内部に滲入する酸と物理的に分離しやすくなり、酸と混和されにくくなる事を示唆している。
なお、DHA、米胚芽油、ビタミンE、ビタミンAの4つの油は、薄黄色~濃茶色であったので、カプセル内部の油への酸の滲入による、リトマス青微粉末の赤色への変化が目視では確認が困難であった。そのため、これら4つの油については、カプセルの外側から顕微鏡で油中に分散したリトマス粒子を拡大して色を確認した。その際の判定の基準は上述と同様である(図5を参照)。
また、ヨウ素価は、油の不飽和度が大きくなるほど値が大きくなる(すなわち、酸化し易い)ので、安定性の指標となるところ、本発明者は、驚くべきことに、不飽和度に関係なく、本発明における多様な油が耐酸性を示すことを見出した。
Claims (14)
- 有効成分と油とを含有するカプセル製剤であって、
前記製剤のカプセルは、水溶性フィルム形成ポリマーおよびジェランガムを含む腸溶性カプセルであり、
前記油は、医薬的または食用的に許容できる油であり、
前記有効成分は、前記油とともに、前記カプセルに封入されている
ことを特徴とする、
カプセル製剤。 - 請求項1に記載のカプセル製剤であって、
前記カプセルは、腸溶性コーティングを含まない、
ことを特徴とする、
カプセル製剤。 - 請求項1または2に記載のカプセル製剤であって、
前記カプセルにおける前記水溶性形成ポリマーと前記ジェランガムとの質量比が、水溶性フィルム形成ポリマー100重量部に対してジェランガムを4~15重量部の質量比である、
ことを特徴とする、
カプセル製剤。 - 請求項1~3のいずれか1項に記載のカプセル製剤であって、
前記カプセルは、ボディ部とキャップ部とを有するハードカプセルであり、
前記ボディ部と前記キャップ部の嵌合部がバンドシールによりシールされている、
ことを特徴とする、
カプセル製剤。 - 請求項1~4のいずれか1項に記載のカプセル製剤であって、
前記油が、植物油、動物油、魚油または鉱物油である、
ことを特徴とする、
カプセル製剤。 - 請求項1~5のいずれか1項に記載のカプセル製剤であって、
前記油が、食用油であって、
前記食用油が、中鎖脂肪酸トリグリセリド、ベニバナ油(サフラワー油)、オリーブ油、大豆油、アマニ油、米胚芽油、小麦胚芽油、ココナッツ油、コーン油、綿実油、パーム油、パーム核油、ピーナッツ油、菜種油、ごま油、ヒマワリ油、アーモンド油、カシュー油、ヘーゼルナッツ油、マカダミアナッツ油、モンゴンゴ油、ペカン油、松の実油、ピスタチオ油、クルミ油、ヒョウタン実油、バッファローカボチャ油、カボチャ実油、スイカ実油、アサイーベリーエキス、カシスオイル、ルリジサ種子油、月見草油、アマランサスオイル、あんず油、リンゴ油、アルガンオイル、アーティチョーク油、アボガド油、ババスオイル、モリンガ油、ケープ栗油、キャロブオイル、コフネヤシ油、コリアンダー油、ディカ油、アマナズナ油、グレープシードオイル、ヘンプ・オイル、カポック実油、ラッレマンチアオイル、マルーラ油、メドウフォーム油、カラシ油、オクラ油(ハイビスカス油)、パパイヤ油、エゴマ油(シソ油)、ケシ油、プルーン油、キヌア油、ニガー種子油、ツバキ油(カメリア油)、アザミ油、トマト油、ノコギリヤシ油、クリル油(オキアミ油)、ボラージ油、ドコサヘキサエン酸(DHA)、エイコサペンタエン酸(EPA)、ビタミンA油、ビタミンD油、ビタミンE油、ビタミンK油、レシチン及びこれらの任意の組合せからなる群から選択される、
ことを特徴とする、
カプセル製剤。 - 請求項1~6のいずれか1項に記載のカプセル製剤であって、
前記カプセルに封入された全内容物における油の量が40質量%以上である、
ことを特徴とする、
カプセル製剤。 - 請求項1~7のいずれか1項に記載のカプセル製剤であって、
前記有効成分は、前記油に分散または溶解している、
ことを特徴とする、
カプセル製剤。 - 請求項1~8のいずれか1項に記載のカプセル製剤であって、
さらに、医薬的または食品的に許容できる界面活性剤が前記カプセルに含まれている、
ことを特徴とする、
カプセル製剤。 - 請求項9に記載のカプセル製剤であって、
前記有効成分は、前記界面活性剤によって前記油に乳化している、
ことを特徴とする、
カプセル製剤。 - 請求項1~10のいずれか1項に記載のカプセル製剤であって、
前記有効成分は、医薬、健康食品、ペプチド類、アミノ酸類、タンパク質類、糖タンパク質類、酵素発酵食品類、酵素類、補酵素類、ビタミン類、ミネラル類、生菌類、植物抽出物、天然有機物、またはこれらの任意の組合せである、
ことを特徴とする、
カプセル製剤。 - 有効成分と油とを含有するカプセル製剤を製造する方法であって、
ここで、
前記製剤のカプセルは、水溶性フィルム形成ポリマーおよびジェランガムを含む腸溶性カプセルであり、
前記油は、医薬的または食用的に許容できる油であり、
前記方法は、以下の工程、
前記有効成分を前記油に分散または溶解させる工程、および
前記有効成分が分散された前記油を前記カプセルに封入する工程、
を含む、
ことを特徴とする、
ハードカプセル製剤を製造する方法。 - 請求項12に記載のカプセル製剤を製造する方法であって、
前記カプセルは、ボディ部とキャップ部とを有するハードカプセルであり、
前記カプセルに封入する工程の後に、前記ボディ部とキャップ部との嵌合部をバンドシールによりシールする工程、
をさらに含む、
カプセル製剤を製造する方法。 - 請求項12または13に記載のカプセル製剤を製造する方法によって製造された、カプセル製剤。
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EP14898418.0A EP3181125A4 (en) | 2014-07-31 | 2014-07-31 | Capsule formulation |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5632413A (en) * | 1979-08-24 | 1981-04-01 | Shionogi & Co Ltd | Enteric hard capsule |
JPH07196478A (ja) * | 1993-12-30 | 1995-08-01 | Hajime Sugii | 安全性の高い食品及び医薬品用ソフトカプセル |
JP2010202550A (ja) * | 2009-03-02 | 2010-09-16 | Qualicaps Co Ltd | 腸溶性カプセル |
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AU2010299527A1 (en) * | 2009-09-24 | 2012-04-19 | Capsugel Belgium Nv | Acid resistant capsules |
EP2866836A1 (en) * | 2012-07-02 | 2015-05-06 | DSM IP Assets B.V. | Capsules containing thymoquinone |
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2014
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5632413A (en) * | 1979-08-24 | 1981-04-01 | Shionogi & Co Ltd | Enteric hard capsule |
JPH07196478A (ja) * | 1993-12-30 | 1995-08-01 | Hajime Sugii | 安全性の高い食品及び医薬品用ソフトカプセル |
JP2010202550A (ja) * | 2009-03-02 | 2010-09-16 | Qualicaps Co Ltd | 腸溶性カプセル |
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US10874619B2 (en) | 2009-09-24 | 2020-12-29 | Capsugel Belgium, NV | Acid resistant capsules |
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EP3181125A4 (en) | 2018-01-17 |
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