JPH02223530A - Interferon preparation for nasal administration - Google Patents
Interferon preparation for nasal administrationInfo
- Publication number
- JPH02223530A JPH02223530A JP1292893A JP29289389A JPH02223530A JP H02223530 A JPH02223530 A JP H02223530A JP 1292893 A JP1292893 A JP 1292893A JP 29289389 A JP29289389 A JP 29289389A JP H02223530 A JPH02223530 A JP H02223530A
- Authority
- JP
- Japan
- Prior art keywords
- interferon
- fatty acid
- ifn
- nasal
- sucrose fatty
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 102000014150 Interferons Human genes 0.000 title claims abstract description 32
- 108010050904 Interferons Proteins 0.000 title claims abstract description 32
- 229940079322 interferon Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- -1 sucrose fatty acid ester Chemical class 0.000 claims abstract description 24
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 23
- 239000000194 fatty acid Substances 0.000 claims abstract description 23
- 229930195729 fatty acid Natural products 0.000 claims abstract description 23
- 229930006000 Sucrose Natural products 0.000 claims abstract description 19
- 239000005720 sucrose Substances 0.000 claims abstract description 19
- 102000006992 Interferon-alpha Human genes 0.000 abstract description 13
- 108010047761 Interferon-alpha Proteins 0.000 abstract description 13
- 210000002850 nasal mucosa Anatomy 0.000 abstract description 10
- 108090000467 Interferon-beta Proteins 0.000 abstract description 5
- 108010074328 Interferon-gamma Proteins 0.000 abstract description 5
- 102000003996 Interferon-beta Human genes 0.000 abstract description 2
- 102000008070 Interferon-gamma Human genes 0.000 abstract description 2
- 229940124532 absorption promoter Drugs 0.000 abstract description 2
- 150000002148 esters Chemical class 0.000 abstract description 2
- 229960003130 interferon gamma Drugs 0.000 abstract description 2
- 229960001388 interferon-beta Drugs 0.000 abstract description 2
- 239000000470 constituent Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 38
- 238000009472 formulation Methods 0.000 description 30
- 230000000052 comparative effect Effects 0.000 description 18
- 239000012086 standard solution Substances 0.000 description 16
- 238000010521 absorption reaction Methods 0.000 description 15
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- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
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- 235000010355 mannitol Nutrition 0.000 description 7
- 210000003928 nasal cavity Anatomy 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
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- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
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- 239000011780 sodium chloride Substances 0.000 description 3
- 241000700159 Rattus Species 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
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- ZPVGIKNDGJGLCO-VGAMQAOUSA-N [(2s,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)O[C@@]1([C@]2(CO)[C@H]([C@H](O)[C@@H](CO)O2)O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O ZPVGIKNDGJGLCO-VGAMQAOUSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
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- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 231100000017 mucous membrane irritation Toxicity 0.000 description 2
- 229940049964 oleate Drugs 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
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- 102000003390 tumor necrosis factor Human genes 0.000 description 2
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
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- 102000015696 Interleukins Human genes 0.000 description 1
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- 229930195725 Mannitol Natural products 0.000 description 1
- 102400000050 Oxytocin Human genes 0.000 description 1
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 description 1
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
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- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
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- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
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Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明はインターフェロン経鼻投与用製剤、より詳しく
は粉末形態又は液状形態で鼻腔内に噴霧もしくは滴下投
与により経鼻投与されるインターフェロン経鼻投与用製
剤に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a formulation for intranasal administration of interferon, more specifically, a formulation for intranasal administration of interferon which is administered in powder or liquid form by spraying or dropping into the nasal cavity. Regarding.
従来技術とその課題
インターフェロン（ＩＦＮ）は、抗ウィルス作用、抗腫
瘍作用、免疫増強作用等の多くの臨床的効果を持ち、抗
ウィルス剤、抗ガン剤等として開発されてきた生理活性
物質であるが、該ＩＦＮを含有する製剤は有効成分とす
るＩＦＮがプロテアーゼ等により瞬時に失活するポリペ
プチドであることやその分子量が巨大で、消化管、経皮
、経粘膜からの吸収が困難であること等から、静注、筋
注、皮下注剤等の注射用製剤形態に限られていた。Prior art and its challenges Interferon (IFN) is a physiologically active substance that has many clinical effects such as antiviral, antitumor, and immune-enhancing effects, and has been developed as an antiviral agent, anticancer agent, etc. However, the active ingredient in preparations containing IFN is a polypeptide that is instantly deactivated by proteases, etc., and its molecular weight is huge, making it difficult to absorb through the gastrointestinal tract, transdermis, or transmucosal membrane. For this reason, it has been limited to injectable formulations such as intravenous, intramuscular, and subcutaneous injections.
かかる注射剤の投与は患者に対して大きな苦痛を強いる
他、在宅治療を困難とし極めて不便であり、該注射剤以
外のより簡便な投与剤型の開発が当業界で熱望され、種
々研究されつつある。その具体的剤型の一つに経鼻投与
剤があり、これについては例えば特開昭６２−２０７２
２６号公報等に報告が見られるが、いずれもＩＦＮと併
用される吸収促進剤としての物質が、それ自体極めて高
い粘膜刺激性を有しており、比較的高いＩＦＮ吸収促進
効果は示すものの経鼻投与用製剤としての実用性は尚乏
しい現状にある。The administration of such injections not only causes great pain to the patient, but also makes home treatment difficult and extremely inconvenient.Therefore, the industry is eager to develop a simpler administration form other than injections, and various studies are being carried out. be. One of the specific dosage forms is nasal administration, which is described in Japanese Patent Publication No. 62-2072, for example.
There are reports in Publication No. 26, etc., but in both cases, the substances used as absorption enhancers in combination with IFN have extremely high mucosal irritation properties, and although they show a relatively high effect of promoting IFN absorption, Practicality as a formulation for nasal administration is still poor.
課題を解決するだめの手段
本発明者の目的は、ＩＦＨの鼻粘膜から吸収性に優れ、
しかも鼻粘膜に対する刺激性の殆んどない安全性の高い
ＩＦＮ経鼻投与用製剤を提供することにある。Means to Solve the Problem The purpose of the present inventor is to provide IFH with excellent absorbability from the nasal mucosa.
Moreover, it is an object of the present invention to provide a highly safe formulation for nasal administration of IFN that is hardly irritating to the nasal mucosa.
本発明は薬理的有効量のＩＦＮと共にショ糖脂肪酸エス
テル類を含有することを特徴とする経鼻投与用製剤に係
わる。The present invention relates to a formulation for nasal administration characterized by containing a pharmacologically effective amount of IFN and sucrose fatty acid esters.
本発明の研究によれば、ＩＦＮと共に吸収促進剤として
ショ糖脂肪酸エステル類を添加することによりＩＦＮが
鼻粘膜から極めて効率よく吸収され、しかも鼻腔粘膜に
対する組織障害性は低く、生体に対する安全性の極めて
高いＩＦＮ経鼻投与用製剤が得られることが見出された
。本発明はかかる新しい知見に基づき完成されたもので
ある。According to the research of the present invention, by adding sucrose fatty acid esters as an absorption enhancer together with IFN, IFN can be absorbed extremely efficiently from the nasal mucosa, and the tissue damage to the nasal mucosa is low, making it safe for living organisms. It has been found that a very high IFN formulation for nasal administration is obtained. The present invention was completed based on this new knowledge.
本発明に係わる如き経鼻投与用製剤は、薬物等を含有す
る溶液或いは粉末固型物を、適当な投与器具、例えばス
プレーポンプ、エアゾール、ネブライザー粉末吸引器具
等を用いて、鼻腔より吸弓させて鼻腔粘膜等に上記薬物
を付着させ該鼻粘膜より該薬物を吸収させるものであり
、本発明は上記薬物としてＩＦＮを利用した経鼻投与用
製剤を提供するものであって、特に上記した特定の吸収
促進剤を配合することによって、ＩＦＨの吸収を効率よ
く促進し、しかも鼻粘膜刺激性の極めて軽微な上記製剤
を提供するものである。In the preparation for nasal administration according to the present invention, a solution or solid powder containing a drug, etc. is sucked into the nasal cavity using an appropriate administration device, such as a spray pump, aerosol, or nebulizer powder suction device. The above-mentioned drug is attached to the nasal mucosa and the like, and the drug is absorbed through the nasal mucosa.The present invention provides a preparation for nasal administration that utilizes IFN as the above-mentioned drug. The present invention provides the above-mentioned formulation which efficiently promotes the absorption of IFH and has very little irritation to the nasal mucosa.
本発明に用いられるＩＦＮは、インターフェロンα（Ｉ
ＦＮ−α）、インターフェロンβ（Ｉ ＦＮ−β）及び
インターフェロンγ（Ｉ ＦＮγ）から選択される少な
くとも１種であればよく、之等はいずれも公知である。The IFN used in the present invention is interferon α (I
It may be at least one selected from FN-α), interferon β (IFN-β), and interferon γ (IFNγ), all of which are known.
尚、本発明の経鼻投与用製剤は上記ＩＦＮのみならず種
々の生理活性ペプチド類にも適用できる。之等生理活性
ペプチド類としては、例えばインシュリン、カルシトニ
ン、黄体ホルモン放出ホルモン、成長ホルモン、オキシ
トシン、パップレシン、デスモプレシン等のホルモン類
、インフルエンザワクチン、Ｂ型肝炎ワクチン、百日咳
ワクチン等のワクチン類、ウロキナーゼ、組織プラスミ
ノーゲン活性・化因子等の酵素蛋白類、インターロイキ
ン、腫瘍壊死因子（ＴＮＦ） 、免疫グロブリン、血液
凝固第■因子等の生理活性蛋白類等を例示できる。The formulation for nasal administration of the present invention can be applied not only to the above-mentioned IFN but also to various physiologically active peptides. Examples of such physiologically active peptides include hormones such as insulin, calcitonin, progestin-releasing hormone, growth hormone, oxytocin, pap pressin, and desmopressin, vaccines such as influenza vaccine, hepatitis B vaccine, and pertussis vaccine, urokinase, and tissue. Examples include enzyme proteins such as plasminogen activating factor, physiologically active proteins such as interleukin, tumor necrosis factor (TNF), immunoglobulin, and blood coagulation factor (III).
また本発明において吸収促進剤として用いられるショ糖
脂肪酸エステル類は、そのエステル構成成分である脂肪
酸成分が炭素数８〜２２であるショ糖脂肪酸エステル類
から選択される少なくとも１種であるのがよく、特に上
記脂肪酸成分の炭素数は１２〜１８の範囲にあるのが好
ましい。２等シヨ糖脂肪酸エステル類としても公知のも
のをいずれも使用できる。また２等エステル類を構成す
る脂肪酸成分は、飽和脂肪酸でも不飽和脂肪酸でもよく
、直鎖のみならず分枝鎖であってもよいが、特に直鎖飽
和脂肪酸であるのが好ましい。Further, the sucrose fatty acid ester used as an absorption enhancer in the present invention is preferably at least one selected from sucrose fatty acid esters whose fatty acid component, which is an ester component, has 8 to 22 carbon atoms. In particular, the number of carbon atoms in the fatty acid component is preferably in the range of 12 to 18. Any known secondary sucrose fatty acid esters can be used. Further, the fatty acid component constituting the secondary esters may be a saturated fatty acid or an unsaturated fatty acid, and may be not only a straight chain but also a branched chain, but a straight chain saturated fatty acid is particularly preferred.
本発明経鼻投与用製剤中に配合されるべき上記ＩＦＮ及
び吸収促進剤としてのショ糖脂肪酸エステル類の量は、
之等各成分の種類により若干異なり、これらの種類に応
じてそれぞれ適当に決定できるが、一般にＩＦＮは製剤
中に１０３〜１０９国際単位（ＩＵ）程度の範囲で配合
されるのが適当である。またショ糖脂肪酸エステル類は
製剤中に通常０．０５ ｖ／ｖ％〜１０ｖノｖ％、好ま
しくは０．１〜５． Ｏｗ／ｖ％の範囲となる濃度で
配合されるのが適当である。The amounts of the above-mentioned IFN and sucrose fatty acid esters as an absorption enhancer to be incorporated into the nasal preparation of the present invention are as follows:
These may vary slightly depending on the type of each component, and can be determined appropriately depending on the type of each component, but in general, it is appropriate to mix IFN in the formulation in a range of about 103 to 109 international units (IU). In addition, sucrose fatty acid esters are usually contained in the preparation at a concentration of 0.05 v/v% to 10 v/v%, preferably 0.1 to 5.0 v/v%. It is appropriate to mix it at a concentration within the range of Ow/v%.
本発明経鼻投与用製剤は、その製剤形態に応じて公知の
各種手段に従い製造することができる。The formulation for nasal administration of the present invention can be manufactured according to various known methods depending on the formulation form.
例えば液剤形態の製剤はＩＦＮと吸収促進剤としてのシ
ョ糖脂肪酸エステル類とを、水又は経鼻投与用製剤に通
常許容される有機溶媒を含む水溶液等に適宜混合、溶解
或いは乳化、分散させることにより製造することができ
、この際必要に応じて薬学上許容される緩衝剤、安定化
剤、保存剤、等張化剤、増粘剤等の各種の添加剤を適宜
加えることもできる。また、粉末等の固剤形態の製剤も
、常法に従う粉末化手段により調製できる。For example, for preparations in liquid form, IFN and sucrose fatty acid esters as absorption enhancers are appropriately mixed, dissolved, emulsified, or dispersed in water or an aqueous solution containing an organic solvent that is normally acceptable for preparations for nasal administration. At this time, various additives such as pharmaceutically acceptable buffers, stabilizers, preservatives, tonicity agents, thickeners, etc. can be added as necessary. Further, solid preparations such as powders can also be prepared by powdering methods according to conventional methods.
かくして得られる本発明の経鼻投与用製剤は、その製剤
形態に応じて、通常のこの種の製剤と同様に、各種患者
にその有効量を経鼻的に投与され、所望の薬理効果を奏
し得る。特に本発明製剤は鼻粘膜刺激性が顕著に低減さ
れているため比較的多量の投与も可能であり、また特定
の吸収促進剤の配合に基づいてその吸収性が改善されて
いるため、比較的少量の投与によって充分な薬理効果を
奏し得る利点がある。The thus obtained nasal preparation of the present invention can be nasally administered in an effective amount to various patients in the same way as ordinary preparations of this type, depending on its formulation form, and can exert the desired pharmacological effect. obtain. In particular, the formulation of the present invention has markedly reduced nasal mucosal irritation, so it can be administered in a relatively large amount, and its absorption has been improved based on the combination of a specific absorption enhancer, so it is relatively easy to administer. It has the advantage that a sufficient pharmacological effect can be achieved by administering a small amount.
実 施 例
以下、本発明を更に詳しく説明するため実施例、比較例
及び試験例を挙げるが、本発明は之等に限定されるもの
ではない。尚、各側において用いた薬剤は以下の通りで
ある。EXAMPLES Examples, comparative examples, and test examples are given below to explain the present invention in more detail, but the present invention is not limited thereto. The drugs used on each side are as follows.
１）ＩＦＮ−α標準液：
ヒトＢＡＬＬ−１細胞由来のＩＦＮ（比活性５０００万
ＩＵ／ｍｇ）であり、安定化剤としてヒト血清アルブミ
ン（０、１ｗ／ｖ％）を含有するリン酸緩衝液（ｐＨ６
）に溶解され、Ｉ Ｆ Ｎ −ａを３００ｏ万ＩＵ／ｍ
Ｑの濃度で含有する標準溶液［株式会社林原生物化学研
究所製］。1) IFN-α standard solution: IFN-α derived from human BALL-1 cells (specific activity 50 million IU/mg), phosphate buffer containing human serum albumin (0, 1 w/v%) as a stabilizer (pH6
), 3 million IU/m of I F N -a
A standard solution containing the concentration of Q [manufactured by Hayashibara Biochemical Research Institute Co., Ltd.].
２）ＩＦＮ−β標準液：
ヒト線維芽細胞由来のＩＦＮ（比活性
１０００万ＩＵ／ｍｇ）を３００万ＩＵ／バイアル及び
安定化剤としてのヒト血清アルブミンを９ ｍｇ／バイ
アル含有する凍結乾燥製剤［東し株式会社製］。2) IFN-β standard solution: Freeze-dried preparation containing 3 million IU/vial of human fibroblast-derived IFN (specific activity 10 million IU/mg) and 9 mg/vial of human serum albumin as a stabilizer [ Manufactured by Toshi Co., Ltd.].
３）ＩＦＮ−γ標準液：
ヒトＨＢＬ−３８細胞由来のＩＦＮ（比活性１０００万
ＩＵ／ｍｇ）であり、安定化剤としてヒト血清アルブミ
ン０． １ｗ／ｖ％を含有するリン酸緩衝液（ｐＨ７，
２）に溶解され、ＩＦＮ−γを３０００万ＩＵ／ｍｏ（
７）濃度で含有する標準溶液［株式会社林原生物化学研
究所製コ。3) IFN-γ standard solution: IFN derived from human HBL-38 cells (specific activity: 10 million IU/mg), containing 0.0% human serum albumin as a stabilizer. Phosphate buffer (pH 7,
2) and 30 million IU/mo of IFN-γ (
7) Standard solution containing concentration [manufactured by Hayashibara Biochemical Research Institute Co., Ltd.].
４） シヨ糖脂肪酸エステル：
ショ糖ラウリン酸エステル、ショ糖パルミチン酸エステ
ル、ショ糖ステアリン酸エステル及びショ糖オレイン酸
エステル［いずれも三菱化成食品株式会社製］。4) Sucrose fatty acid ester: Sucrose laurate, sucrose palmitate, sucrose stearate, and sucrose oleate [all manufactured by Mitsubishi Kasei Foods Corporation].
実施例 Ｉ
ＩＦＮ−α標準液５１ＴＩＱにショ糖ラウリン酸エステ
ル５０ｍｇを加えて溶かし、更にＤ−マンニトールを加
えて浸透圧比を２に調節し、凍結乾燥して本発明経鼻投
与用製剤を得た。Example I 50 mg of sucrose laurate was added to IFN-α standard solution 51TIQ and dissolved, D-mannitol was added to adjust the osmotic pressure ratio to 2, and the mixture was lyophilized to obtain a formulation for nasal administration of the present invention. .
この製剤は、用時これに１０ｍ１２の水を加えて溶かし
て投与される。This preparation is administered by dissolving it in 10 ml of water before use.
実施例 ２
ＩＦＮ−α標準液５ｍ１２に１ ｗ／ｖ％シヨ糖パルミ
チン酸エステル溶液５ｍＱを加えた後、Ｄ−マンニトー
ルにより等張として、本発明経鼻投与用製剤を得た。Example 2 After adding 5 mQ of 1 w/v% sucrose palmitate solution to 5 ml of IFN-α standard solution, the mixture was made isotonic with D-mannitol to obtain a formulation for nasal administration of the present invention.
実施例 ３
０、 ５ ｗ／ｖ％シヨ糖ステアリン酸エステル溶液に
ＩＦＮ−α標準液の凍結乾燥粉末を加えて、１５００万
ＩＵ／ｍＱ溶液を作成した。この液をＤマンニトールに
より等張として、本発明経鼻投与用製剤を得た。Example 3 A lyophilized powder of IFN-α standard solution was added to a 0, 5 w/v% sucrose stearate solution to prepare a 15 million IU/mQ solution. This solution was made isotonic with D-mannitol to obtain a formulation for nasal administration of the present invention.
実施例 ４
ＩＦＮ−γ標準液５ｍｆ２に１ ｗ／ｖ％シヨ糖ステア
リン酸エステル溶液５１ＴＩＱを加えた後、Ｄ−マンニ
トールにより等張として、本発明経鼻投与用製剤を得た
。Example 4 After adding 1 w/v% sucrose stearate solution 51TIQ to 5mf2 of IFN-γ standard solution, the mixture was made isotonic with D-mannitol to obtain a formulation for nasal administration of the present invention.
実施例 ５
ＩＦＮ−β標準液に、０． ５ ｗ／ｖ％シヨ糖ステア
リン酸エステル溶液０．２ｍ１２を加えて溶かして、本
発明経鼻投与用製剤を得た。Example 5 0.0% was added to the IFN-β standard solution. 0.2 ml of 5 w/v% sucrose stearate solution was added and dissolved to obtain a formulation for nasal administration of the present invention.
実施例 ６
ＩＦＮ−α標準液５ｍＧに１ ｗ／ｖ％シヨ糖オレイン
酸エステル溶液５ｍＱを加えた後、Ｄ−マンニトールに
より等張として、本発明経鼻投与用製剤を得た。Example 6 After adding 5 mQ of 1 w/v% sucrose oleate solution to 5 mG of IFN-α standard solution, the mixture was made isotonic with D-mannitol to obtain a formulation for nasal administration of the present invention.
実施例 ７
ＩＦＮ−α標準液５ｍＱにショ糖ステアリン酸エステル
５０ｍｇを加えて溶かし、更にＤ−マンニトールを加え
て等張として、凍結乾燥して本発明経鼻投与用製剤を得
た。Example 7 50 mg of sucrose stearate was added to 5 mQ of IFN-α standard solution and dissolved, D-mannitol was added to make the solution isotonic, and the mixture was lyophilized to obtain a formulation for nasal administration of the present invention.
この製剤は、用時これに５戒の水を加えて溶かして投与
される。Before use, this preparation is administered by adding 5 precepts of water to dissolve it.
比較例 Ｉ
ＩＦＮ−α標準液５ｍＱに水５ｖａＱを加えた後、Ｄ−
マンニトールにより等張として、比較経鼻投与用製剤を
得た。Comparative Example I After adding 5 vaQ of water to 5 mQ of IFN-α standard solution, D-
A comparative nasal formulation was made isotonic with mannitol.
比較例 ２
ＩＦＮ−α標準液５岐にポリオキシエチレン（９）ラウ
リルエーテル（ＢＬ−９ＥＸ）５０ｍｇを加えて溶かし
た後、塩化ナトリウムにより等張として、比較経鼻投与
用製剤を得た。Comparative Example 2 50 mg of polyoxyethylene (9) lauryl ether (BL-9EX) was added to and dissolved in the 5-stranded IFN-α standard solution, and the mixture was made isotonic with sodium chloride to obtain a comparative formulation for nasal administration.
比較例 ３
ＩＦＮ−α標準液５ｍＱにグリココール酸ナトリウム５
０ｍｇを加えて溶かした後、塩化ナトリウムにより等張
として、比較経鼻投与用製剤を得た。Comparative Example 3 Sodium glycocholate 5 mQ of IFN-α standard solution
After adding and dissolving 0 mg, the mixture was made isotonic with sodium chloride to obtain a comparative formulation for nasal administration.
比較例 ４
ＩＦＮ−α標準液５ｍ１２にサポニン５０ｍｇを加えて
溶かした後、塩化ナトリウムにより等張として、比較経
鼻投与用製剤を得た。Comparative Example 4 After adding and dissolving 50 mg of saponin in 5 ml of IFN-α standard solution, the mixture was made isotonic with sodium chloride to obtain a comparative nasal preparation.
試験例 Ｉ
ＩＦＮ吸収促進効果試験
ＳＤ系雌雄性ラット体重２００〜３００ｇ）に、ベンド
パルビタールを腹腔内投与（５０ｍｇ／ ｋｇ）し麻酔
した後、頚部を切開し気管にポリエチレンチューブを挿
入し、気道を確保する。食道の一部を切開し、先端を打
栓したポリエチレンチューブを後鼻腔に向けて挿入し、
後鼻腔を密閉する。Test Example I IFN absorption promotion effect test SD male and female rats (body weight 200-300 g) were anesthetized by intraperitoneal administration of bendoparbital (50 mg/kg), the neck was incised, a polyethylene tube was inserted into the trachea, and the airway was ensure that A part of the esophagus is incised and a polyethylene tube with a plugged end is inserted toward the posterior nasal cavity.
Seal the posterior nasal cavity.
前記実施例及び比較例で作成した各製剤を０、 １ｍ１
２／ｋｇの容量で鼻腔内に投与し、投与後続時的に頚静
脈より採血し、血清中のＩＦＮの抗ウィルス活性を測定
する。0, 1 ml of each formulation prepared in the above Examples and Comparative Examples
The drug is administered intranasally at a volume of 2/kg, and blood is collected from the jugular vein at intervals after administration to measure the antiviral activity of IFN in the serum.
結果を第１表に示す。The results are shown in Table 1.
第 １
表
尚、Ｎ、Ｄ、は検出不能を示す。また上記結果は試験回
数３回の平均値である。In Table 1, N and D indicate undetectable. Furthermore, the above results are the average values of three tests.
上記結果より、脂肪酸成分が炭素数１２〜１８であるシ
ョ糖脂肪酸エステルを添加した本発明の経鼻投与用製剤
は、いずれもＩＦＮ単独の比較製剤（比較１）に比べ極
めて高いＩＦＨの鼻粘膜からの吸収性を示し、これは従
来公知の他の吸収促進剤を添加配合した比較製剤（比較
２〜４）と比較しても同等或いはそれをも凌ぐことが判
る。From the above results, the formulations for nasal administration of the present invention containing a sucrose fatty acid ester having a fatty acid component of 12 to 18 carbon atoms have extremely high IFH in the nasal mucosa compared to the comparative formulation containing only IFN (Comparison 1). When compared with comparative preparations (Comparisons 2 to 4) containing other conventionally known absorption enhancers, it can be seen that this is equivalent to or even better than that.
試験例 ２
吸収促進剤の蛋白溶出試験
鼻粘膜組織に対する吸収促進剤の刺激性試験を鼻腔還流
法による蛋白溶出量の測定により以下の通り実施した。Test Example 2 Protein Elution Test of Absorption Promoters A test of the irritation of absorption enhancers to nasal mucosal tissue was carried out as follows by measuring the amount of protein elution by the nasal perfusion method.
即ち、ＳＤ系雌雄性ラット体重２００〜３００ｇ）にベ
ンドパルビタールを腹腔内投与（５０ｍｇ／ｋｇ） し
て麻酔した後、頚部を切開し気管にポリエチレンチュー
ブを挿入し、気道を確保する。更に食道の一部を切開し
、ポリエチレンチューブを後鼻腔に向けて挿入し、ポリ
エチレンチューブを後鼻腔に連結し、該チューブより、
前記実施例及び比較例１で作成した各製剤又は比較例２
〜４で得た各製剤を更に生理食塩水で２倍に希釈した製
剤［但しこの場合、吸収促進剤濃度は０． ５ ｗ／ｖ
％一定（ＩＦＮを効率よく吸収させるための最小濃度）
とする］のそれぞれ２２０ｍを送液ポンプにより流量１
１ＴＩＱ／分で送液し、３０分間鼻腔内を還流させる。That is, SD male and female rats (body weight 200 to 300 g) are anesthetized by intraperitoneal administration of bendoparbital (50 mg/kg), and then the neck is incised and a polyethylene tube is inserted into the trachea to secure the airway. Furthermore, a part of the esophagus is incised, a polyethylene tube is inserted toward the posterior nasal cavity, the polyethylene tube is connected to the posterior nasal cavity, and from the tube,
Each formulation prepared in the above Examples and Comparative Example 1 or Comparative Example 2
Preparations obtained by further diluting each preparation obtained in steps 4 to 4 with physiological saline [however, in this case, the absorption enhancer concentration was 0. 5w/v
% constant (minimum concentration for efficient absorption of IFN)
] respectively 220m with a flow rate of 1 using a liquid pump.
The solution is delivered at a rate of 1 TIQ/min, and the nasal cavity is allowed to reflux for 30 minutes.
還流開始後１５分及び３０分に還流液の一部を採取し、
還流液中の蛋白溶出量を求め、鼻腔粘膜組織への刺激性
の強弱を判定した。A portion of the reflux liquid was collected 15 minutes and 30 minutes after the start of reflux,
The amount of protein eluted in the reflux solution was determined, and the strength of irritation to the nasal mucosal tissue was determined.
結果を第２表に示す。The results are shown in Table 2.
耶
表
上記結果より、脂肪酸成分が炭素数１２〜１８であるシ
ョ糖脂肪酸エステルを添加した本発明の経鼻投与用製剤
は、いずれも比較例１（ＩＦＮ単独の比較製剤）に比べ
てわずかに刺激性は強いものの、比較例２〜４（従来公
知の他の吸収促進剤を添加配合した比較製剤）と比較す
れば、はるかに刺激性が弱いことが明らかである。From the above results, it can be seen that the formulations for nasal administration of the present invention containing sucrose fatty acid esters having a fatty acid component of 12 to 18 carbon atoms have a slightly higher level of sterilization compared to Comparative Example 1 (comparative formulation containing IFN alone). Although the irritation is strong, it is clear that the irritation is much weaker when compared with Comparative Examples 2 to 4 (comparative formulations containing other conventionally known absorption enhancers).
（以 上）(Hereafter Up)
Claims (1)
を含有することを特徴とする経鼻投与用製剤。(1) A preparation for nasal administration characterized by containing interferon and sucrose fatty acid esters.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1292893A JPH0651642B2 (en) | 1988-11-14 | 1989-11-09 | Interferon formulation for nasal administration |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28859188 | 1988-11-14 | ||
| JP63-288591 | 1988-11-14 | ||
| JP1292893A JPH0651642B2 (en) | 1988-11-14 | 1989-11-09 | Interferon formulation for nasal administration |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02223530A true JPH02223530A (en) | 1990-09-05 |
| JPH0651642B2 JPH0651642B2 (en) | 1994-07-06 |
Family
ID=26557242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1292893A Expired - Lifetime JPH0651642B2 (en) | 1988-11-14 | 1989-11-09 | Interferon formulation for nasal administration |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0651642B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08283176A (en) * | 1995-04-06 | 1996-10-29 | F Hoffmann La Roche Ag | Interferon solution |
| JP2001240558A (en) * | 2000-02-29 | 2001-09-04 | Nippon Suisan Kaisha Ltd | A solid preparation containing a polyunsaturated fatty acid as a transmucosal absorption enhancer. |
| US8512692B2 (en) | 1996-12-24 | 2013-08-20 | Biogen Idec Ma Inc. | Methods of treating multiple sclerosis with stable liquid interferon-beta formulations |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5910524A (en) * | 1982-07-08 | 1984-01-20 | Toray Ind Inc | Interferon composition and its preparation |
| JPS62185030A (en) * | 1986-02-07 | 1987-08-13 | Toray Ind Inc | Interferon pharmaceutical for nasotracheal administration |
| JPS6339822A (en) * | 1986-08-04 | 1988-02-20 | Yamanouchi Pharmaceut Co Ltd | Transnasal calcitonin agent |
-
1989
- 1989-11-09 JP JP1292893A patent/JPH0651642B2/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5910524A (en) * | 1982-07-08 | 1984-01-20 | Toray Ind Inc | Interferon composition and its preparation |
| JPS62185030A (en) * | 1986-02-07 | 1987-08-13 | Toray Ind Inc | Interferon pharmaceutical for nasotracheal administration |
| JPS6339822A (en) * | 1986-08-04 | 1988-02-20 | Yamanouchi Pharmaceut Co Ltd | Transnasal calcitonin agent |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08283176A (en) * | 1995-04-06 | 1996-10-29 | F Hoffmann La Roche Ag | Interferon solution |
| US8512692B2 (en) | 1996-12-24 | 2013-08-20 | Biogen Idec Ma Inc. | Methods of treating multiple sclerosis with stable liquid interferon-beta formulations |
| US8512691B2 (en) | 1996-12-24 | 2013-08-20 | Biogen Idec Ma Inc. | Stable liquid interferon-beta formulations |
| US8932574B2 (en) | 1996-12-24 | 2015-01-13 | Biogen Idec Ma Inc. | Stable liquid interferon beta formulations |
| US9522174B2 (en) | 1996-12-24 | 2016-12-20 | Biogen Ma Inc. | Stable liquid interferon beta formulations |
| JP2001240558A (en) * | 2000-02-29 | 2001-09-04 | Nippon Suisan Kaisha Ltd | A solid preparation containing a polyunsaturated fatty acid as a transmucosal absorption enhancer. |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0651642B2 (en) | 1994-07-06 |
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