JPH01287041A - Sustained release preparation - Google Patents
Sustained release preparationInfo
- Publication number
- JPH01287041A JPH01287041A JP63116678A JP11667888A JPH01287041A JP H01287041 A JPH01287041 A JP H01287041A JP 63116678 A JP63116678 A JP 63116678A JP 11667888 A JP11667888 A JP 11667888A JP H01287041 A JPH01287041 A JP H01287041A
- Authority
- JP
- Japan
- Prior art keywords
- hyaluronic acid
- insulin
- sustained release
- administration
- salt
- 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.)
- Pending
Links
- 239000003405 delayed action preparation Substances 0.000 title abstract 3
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 36
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 33
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000013543 active substance Substances 0.000 claims abstract description 9
- 238000007918 intramuscular administration Methods 0.000 claims abstract description 6
- 238000013268 sustained release Methods 0.000 claims description 10
- 239000012730 sustained-release form Substances 0.000 claims description 10
- 238000007920 subcutaneous administration Methods 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 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 abstract description 34
- 102000004877 Insulin Human genes 0.000 abstract description 17
- 108090001061 Insulin Proteins 0.000 abstract description 17
- 229940125396 insulin Drugs 0.000 abstract description 17
- 238000002347 injection Methods 0.000 abstract description 13
- 239000007924 injection Substances 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000000243 solution Substances 0.000 abstract description 7
- 239000000725 suspension Substances 0.000 abstract description 6
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3N=CN=C3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 239000000654 additive Substances 0.000 abstract description 2
- 239000000306 component Substances 0.000 abstract 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract 1
- 239000007951 isotonicity adjuster Substances 0.000 abstract 1
- 230000003533 narcotic effect Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract 1
- 239000011701 zinc Substances 0.000 abstract 1
- 229910052725 zinc Inorganic materials 0.000 abstract 1
- 239000008280 blood Substances 0.000 description 20
- 210000004369 blood Anatomy 0.000 description 20
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-MNSSHETKSA-N 0.000 description 3
- 229940099552 hyaluronan Drugs 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- NOESYZHRGYRDHS-ZYCCASTOSA-N 8a-l-threonine-10a-l-isoleucine-insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 NOESYZHRGYRDHS-ZYCCASTOSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 230000012666 negative regulation of transcription by glucose Effects 0.000 description 1
- 229950009610 neutral insulin injection Drugs 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000003357 wound healing promoting agent Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は、徐放性製剤に関する。[Detailed description of the invention] [Industrial application field] The present invention relates to sustained release formulations.
［従来の技術］
最近、製剤の設計に当たり、製剤の活性成分を体内また
は体表面上で徐々に放出する試み即ち徐放化が活発に研
究されてきている。しかし、現在までのところ、皮下ま
たは筋肉内投与に適した徐放性製剤で成功した例は殆ど
見られない。[Prior Art] Recently, in designing pharmaceutical preparations, attempts to gradually release the active ingredients of the preparation into the body or onto the body surface, that is, sustained release, have been actively researched. However, to date, there have been few successful examples of sustained release formulations suitable for subcutaneous or intramuscular administration.
［発明の概要］
周知の通り、ヒアルロン酸は、天然に存在する酸性ムコ
多糖の一つであり、動物結合組織に広く分布している。[Summary of the Invention] As is well known, hyaluronic acid is one of the naturally occurring acidic mucopolysaccharides and is widely distributed in animal connective tissue.
その生体適合性は既に認められており、天然保湿剤とし
て化粧品に用いられ、さらに関節機能改菩のための関節
腔内注射剤（商標名ＡＲＴＺ、科研爬薬）、眼内注射剤
（商標名オペガン。Its biocompatibility has already been recognized, and it is used in cosmetics as a natural moisturizer, as well as intra-articular injections (trade name: ARTZ, Kaken Ryuyaku) and intraocular injections (trade name: Opegan.
参人１薬）として利用されている。ヒアルロン酸の水溶
液は、高い粘稠性を示し、これはヒアルロン酸の分子量
や濃度、ｐ）Ｉ、イオン強度等により制御が可能である
。It is used as a medicine. An aqueous solution of hyaluronic acid exhibits high viscosity, which can be controlled by controlling the molecular weight and concentration of hyaluronic acid, p)I, ionic strength, and the like.
本発明者らは５ヒアルロン酸のこの特性を利用して製剤
からの薬物の放出の制御を行うことについて１種々検討
した結果、本発明を見い出した。The present inventors have discovered the present invention as a result of various studies on controlling the release of drugs from preparations by utilizing this property of 5-hyaluronic acid.
即ち、本発明は皮下または筋肉内投与に適した医薬活性
物質及びヒアルロン酸もしくはその製薬上許容しつる塩
を含む徐放性製剤に関する。That is, the present invention relates to a sustained release formulation containing a pharmaceutically active substance and hyaluronic acid or a pharmaceutically acceptable salt thereof suitable for subcutaneous or intramuscular administration.
本発明に用いられつるヒアルロン酸としてはヒアルロン
酸、またはヒアルロン酸とアルカリもしくはアルカリ土
類金属、アルミニウム、アンモニウムまたは置換アンモ
ニウムとの塩を含む（以下、ヒアルロン酸またはその塩
とする）６本発明で用いられるヒアルロンｆは、好まし
くは約５６万〜２４０万の範囲の分子量を有する。ヒア
ルロン酸の安全性は高く、例えばその皮下投与における
ＬＤｓｏは、物理的投与限界以上（＞１５００ｍｇ／ｋ
ｇ） ［赤坂日出道ら、「バイオポリマーとしてのヒ
アルロン酸の特性と応用」フレグランスジャーナル、Ｎ
ｏ、７８．４２−４７ページ（１９８６）］である。The hyaluronic acid used in the present invention includes hyaluronic acid or a salt of hyaluronic acid and an alkali or alkaline earth metal, aluminum, ammonium, or substituted ammonium (hereinafter referred to as hyaluronic acid or a salt thereof). The hyaluron f used preferably has a molecular weight in the range of about 560,000 to 2,400,000. The safety of hyaluronic acid is high, for example, the LDso in its subcutaneous administration exceeds the physical administration limit (>1500mg/kg).
g) [Hidemichi Akasaka et al., “Characteristics and Applications of Hyaluronic Acid as a Biopolymer” Fragrance Journal, N
o, 78, pp. 42-47 (1986)].
また１本発明で用いられつる医薬活性物質としては、皮
下または筋肉内投与されうるちのであれば、いかなるも
のでもよく１例えば抗生物質、抗炎症剤、抗菌剤、抗ウ
ィルス剤、抗感染剤、抗腫瘍剤、細胞増殖抑制剤、創傷
治癒剤、麻酔剤、循環器官用薬、消化器官用薬、ホルモ
ン剤、ビタミン剤等が挙げられる。これらの薬剤のなか
で、インスリン、結晶性インスリン亜鉛５非品性インス
リン亜鉛が、従来行われている投与方法の点から本発明
にとり好ましい。周知のように、インスリンは、１ａ尿
病の治療に用いられてきているが、胃液で分解されるた
め、一般に皮下投与（場合により一日数回）されている
、そのため、無品性インスリン亜鉛水性懸濁注射液、結
晶性インスリン亜鉛水性悲濁注射液などが開発されてき
ているが。The pharmaceutically active substance used in the present invention may be any substance that can be administered subcutaneously or intramuscularly, such as antibiotics, anti-inflammatory agents, antibacterial agents, antiviral agents, anti-infective agents, Examples include antitumor agents, cell growth inhibitors, wound healing agents, anesthetics, drugs for the circulatory system, drugs for the digestive system, hormones, vitamins, and the like. Among these drugs, insulin, crystalline insulin zinc 5, and non-grade insulin zinc are preferred for the present invention in terms of conventional administration methods. As is well known, insulin has been used to treat 1a urine disease, but because it is degraded by gastric juice, it is generally administered subcutaneously (sometimes several times a day). Suspension injections, crystalline insulin zinc aqueous injections, etc. have been developed.
十分とはいえない、また皮下投与されたインスリンは、
その生物学的利用能が静注に比べて５０〜６０％とされ
ており、そのためにも徐放化は有意義といえる。Insulin administered subcutaneously is not sufficient.
Its bioavailability is said to be 50-60% compared to intravenous injection, and for this reason sustained release can be said to be significant.
本発明における皮下または筋肉内投与としては、例えば
注射または潅流による皮下投与が挙げられる。動物の皮
下組織は、結合組織が疎に集まっており、多量の薬液の
注入が可能であるとされている［「生物薬剤学実験マニ
ュアル」徴募 茂編。Subcutaneous or intramuscular administration in the present invention includes, for example, subcutaneous administration by injection or perfusion. The subcutaneous tissue of animals is made up of loose connective tissue, and it is said that it is possible to inject large amounts of drug solutions [``Biopharmaceutical Experiment Manual'' edited by Shigeru Shigeru.
７６ページ、清至書院（１９’８５）］、そのため。76 pages, Seishi Shoin (19'85)], therefore.
徐徐放化剤としての注射剤を考えたとき、徐放化により
一回の薬物投与量が多くなり、また著しい徐放化を期待
する場合、より多量の徐放用材料を使用する必要がある
ことから、皮下投与が都合がよいことになる。When considering an injection as a sustained release agent, sustained release increases the amount of drug administered at one time, and if significant sustained release is expected, it is necessary to use a larger amount of sustained release material. This makes subcutaneous administration convenient.
本発明の製剤は、前述の医薬活性物質とヒアルロン酸ま
たはその塩とを含むが、好ましくは、両者が単位投与物
中に存在するようにする０例えば、アンプルまたはバイ
アル中に滅菌水または滅菌生理食塩水に溶解または懸濁
して両者が存在するようにする。この場合、医薬活性物
質の溶液または懸濁液とヒアルロン酸またはその塩の溶
液または懸濁液とを混合して調製しても、または医薬活
性物質の溶液または懸濁液にヒアルロン酸またはその塩
の粉末を加えて調製しても、またはその逆でもよい、こ
の単位投与物には、従来用いられている添加物例えば等
張化剤または局所麻酔剤などを含んでも良い、また、言
うまでもなく、投与直前に医薬活性物質とヒアルロン酸
またはその塩とを混合して溶液または懸濁液とし、これ
を用いてもよい、医薬活性物質とヒアルロン酸またはそ
の塩との重量比は、医薬活性物質の性質により広範囲に
変化しつる０例えば、医薬活性物質対ヒアルロン酸また
はその塩の比は、０．０１：１〜１００：］好ましくは
０．０１：ｌ−１ｏｌｌである。The formulations of the invention contain the aforementioned pharmaceutically active substance and hyaluronic acid or a salt thereof, preferably in such a way that both are present in a unit dose, e.g. Dissolve or suspend in saline so that both are present. In this case, it may be prepared by mixing a solution or suspension of the pharmaceutically active substance with a solution or suspension of hyaluronic acid or its salt, or a solution or suspension of the pharmaceutically active substance may be mixed with hyaluronic acid or its salt. It goes without saying that this unit dose, which may be prepared with the addition of a powder of or vice versa, may also contain conventional additives such as tonicity agents or local anesthetics, etc. Immediately before administration, the pharmaceutically active substance and hyaluronic acid or its salt may be mixed to form a solution or suspension, and this may be used. For example, the ratio of pharmaceutically active substance to hyaluronic acid or a salt thereof may vary widely depending on the nature, preferably from 0.01:1 to 100:1.
［実施例ゴ 次に、実施例を示す。[Example Go Next, examples will be shown.
実施例 １
対照とするインスリン注射剤は、ブタ中性インスリン注
射剤（ノボ、アクトラビット、阿Ｃ４０ＩＵ／ｍｌ）を
０ 、５ ＩＵ／ｍｌになるように生理食塩水で稀釈し
た。Example 1 As a control insulin injection, a porcine neutral insulin injection (Novo, Actravit, A-C40 IU/ml) was diluted with physiological saline to a concentration of 0.5 IU/ml.
一方１本発明のヒアルロン酸含有インスリン注射剤は、
前記の稀釈注射液にヒアルロン酸が１％の濃度になるよ
うにヒアルロンａ（平均分子量１４０万、極限粘度）粉
末を加えて調製した。On the other hand, the hyaluronic acid-containing insulin injection of the present invention is
Hyaluronic acid powder (average molecular weight: 1.4 million, intrinsic viscosity) was added to the above-mentioned diluted injection solution so that the concentration of hyaluronic acid was 1%.
これら注射剤を使用して以下の動物実験を行った。The following animal experiments were conducted using these injections.
実験動物としては、正常雄性家兎（日本白色種、体重約
２．１〜２．６ｋｇ）８羽を用い、インスリン単独注射
剤群及びヒアルロン酸・インスリン注射剤群の２群に分
け、各々−群４羽とした。生体内において、摂食後にイ
ンスリンは急激に分泌されるため、投与前２４時間の絶
食を行い、血糖値の変動を避けた。投与量は１両群とも
に０．５ＩＵ／ｋｇとし、背部皮下に投与した（２２Ｇ
、２゜５■１デイスポーザブル注射器、チル七１１）。Eight normal male domestic rabbits (Japanese white breed, weight approximately 2.1-2.6 kg) were used as experimental animals, and they were divided into two groups: an insulin-only injection group and a hyaluronic acid/insulin injection group. There were 4 birds in the group. Since insulin is rapidly secreted in vivo after feeding, subjects were fasted for 24 hours before administration to avoid fluctuations in blood sugar levels. The dose was 0.5 IU/kg for both groups, and it was administered subcutaneously to the back (22G
, 2゜5■1 disposable syringe, chill 711).
採血部位は、耳介静脈とし、投与前次いで投与後０．５
．１．２．３．４．６．８．１２．２４時間に採血し、
血漿中の血Ｕｉ値を測定した。The blood collection site is the auricular vein, and 0.5 minutes before and after administration.
．． Blood was collected at 1.2.3.4.6.8.12.24 hours,
Blood Ui value in plasma was measured.
血糖値測定は、グルコース−Ｂ−テストキット（Ｃ０Ｄ
−ＰＯＤ法、和光補薬１１）により行った。Blood sugar level measurement is performed using the Glucose-B-Test Kit (C0D
-Performed by POD method, Wako supplementary medicine 11).
データとしては、投与前の血糖値を１００％として、各
測定時の血糖変化率（％）を算出した。As for the data, the blood sugar change rate (%) at each measurement was calculated with the blood sugar level before administration as 100%.
さらに、投与後１２時間までの血糖値の総変化率（％）
を次式から求めた。Furthermore, the total change rate (%) of blood sugar level up to 12 hours after administration.
was calculated from the following equation.
投与後１２時間までの血糖総変化率（％）インスリン単
独群及びヒアルロン酸併用群より得られた血糖変化率の
経時的変化を表１及び第１図に示した。Total blood sugar change rate (%) up to 12 hours after administration The time-course changes in blood sugar change rate obtained from the insulin alone group and the hyaluronic acid combination group are shown in Table 1 and Figure 1.
及−−１
時間（時） ４ンｌＴＪン単独投与 ヒ？ロン酸併
用投与平均血糖変化 平均血糖変化
±Ｓ、Ｅ、 ％ 皇」ニＬヱエエ３」−ｏ
１００．ｏ １
００．００．５ ９５．６± １４．３
７５．４± ６．６１ ６１．
４± ８．５ ６１１１．８±６．２２
４９．７± ４．８ ６０
．５± ２．５３ ４５．３± ８．２
５７．８± １．６４
４４．２± ５．０ ６１．９± ５．３
６ ４７．９± ４．２
４８．２± ３．９８ ８０．１± １
１．２ ５２．８± ３．７１２
９６．７± ３．４ ４３．２±６
．５１２４ ９６．９± ９．２
１０３．０± ６．８宰：ρ＜ ｏ、ｏ＋ｉた
はρ＜ ０．０５実験の結果から分かるように５インス
リン単独群に比べて、ヒアルロン酸併用群では血糖値の
低下に明らかな持続化が認められる。特に、投与後１２
時間の価では１両者に有意な差が存在する（ｐ＜０．０
１及び０．０５）、インスリン単独群の場合、血糖値の
低下は投与後４時間で最大となり、その後光の血糖値レ
ベルまで回復する。投与後８時間及び１２時間の血糖変
化率はそれぞれ約８０％、約９７％である。ヒアルロン
談併用群では投与後１，２．３及び４時間において血糖
変化率はインスリン単独群より高い価となるが、投与後
８および１２時間では低くなり、それぞれ約５３％、約
４３％である。このように、血糖値の回復がヒアルロン
談併用群において遅延したことは。- 1 hour (hours) Single administration of 4-1TJ h? Average blood sugar change after coadministration of ronic acid Average blood sugar change ±S, E, %
100. o 1
00.00.5 95.6± 14.3
75.4± 6.61 61.
4± 8.5 6111.8±6.22
49.7± 4.8 60
．． 5± 2.53 45.3± 8.2
57.8± 1.64
44.2± 5.0 61.9± 5.3
6 47.9± 4.2
48.2± 3.98 80.1± 1
1.2 52.8± 3.712
96.7± 3.4 43.2±6
．． 5124 96.9± 9.2
103.0 ± 6.8: ρ < o, o + i or ρ < 0.05 As can be seen from the experimental results, the hyaluronic acid combination group showed a clear and sustained decrease in blood sugar levels compared to the insulin alone group. is recognized. In particular, after administration 12
There is a significant difference between the two in terms of time valence (p<0.0
1 and 0.05), in the insulin-alone group, the decrease in blood glucose levels is maximal at 4 hours after administration, and then recovers to light blood glucose levels. The rate of change in blood sugar at 8 hours and 12 hours after administration is about 80% and about 97%, respectively. In the hyaluronan combination group, the blood glucose change rate was higher than the insulin alone group at 1, 2.3, and 4 hours after administration, but it was lower at 8 and 12 hours after administration, approximately 53% and 43%, respectively. . Thus, the recovery of blood sugar levels was delayed in the hyaluronan combination group.
ヒアルロン酸を併用することにより、インスリンの持続
的吸収がなされたことによるものである。This is because continuous absorption of insulin was achieved by using hyaluronic acid in combination.
また、投与後１２時間までの血糖総変化率を両群につい
て求めると、インスリン単独群では３２゜５±３．４％
、ヒアルロン談併用群では４４．６±２．５％となり１
両者の間には有意な差が認められた（ｐ＜０．０５）、
このことが同一投与量において認められたことは、ヒア
ルロン酸が皮下投与におけるインスリンの生物学的利用
能を向上させるのに有効であることを示すものである。In addition, when the total blood glucose change rate up to 12 hours after administration was determined for both groups, it was 32°5 ± 3.4% in the insulin-only group.
, 44.6 ± 2.5% in the hyaluronan combination group, 1
A significant difference was observed between the two (p<0.05),
The fact that this was observed at the same dose indicates that hyaluronic acid is effective in improving the bioavailability of insulin upon subcutaneous administration.
さらに、平均分子量５０万、１００万または２００万の
ヒアルロン酸についても同様な動物実験を行い、これら
の場合でもヒアルロン酸の併用によりインスリンの持続
的吸収が認められた。Furthermore, similar animal experiments were conducted using hyaluronic acid with an average molecular weight of 500,000, 1,000,000, or 2,000,000, and in these cases, sustained absorption of insulin was also observed when hyaluronic acid was used in combination.
第１図は、インスリンの血［１下作用に及ぼすヒアルロ
ン酸の効果を示す。
特許出頭式 株式会社ローマン工業
第 １ 因
＋コインスソンFIG. 1 shows the effect of hyaluronic acid on the blood glucose effect of insulin. Patent Appearance Ceremony Roman Kogyo Co., Ltd. 1st Cause + Coinsson
Claims (1)
ロン酸もしくはその製薬上許容しうる塩を含む徐放性製
剤。A sustained release formulation comprising a pharmaceutically active substance and hyaluronic acid or a pharmaceutically acceptable salt thereof suitable for subcutaneous or intramuscular administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63116678A JPH01287041A (en) | 1988-05-13 | 1988-05-13 | Sustained release preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63116678A JPH01287041A (en) | 1988-05-13 | 1988-05-13 | Sustained release preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01287041A true JPH01287041A (en) | 1989-11-17 |
Family
ID=14693172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63116678A Pending JPH01287041A (en) | 1988-05-13 | 1988-05-13 | Sustained release preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01287041A (en) |
Cited By (18)
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| WO1992006714A1 (en) * | 1990-10-18 | 1992-04-30 | Shiseido Co., Ltd. | Combination of hyaluronic acid with medicinal ingredient and production thereof |
| US5639738A (en) * | 1992-02-20 | 1997-06-17 | Hyal Pharmaceutical Corporation | Treatment of basal cell carcinoma and actinic keratosis employing hyaluronic acid and NSAIDs |
| US5674857A (en) * | 1992-02-20 | 1997-10-07 | Hyal Pharmaceutical Corporation | Use of hyaluronic acid to repair ischemia reperfusion damage |
| US5733891A (en) * | 1990-10-18 | 1998-03-31 | Shiseido Co., Ltd. | Compound for medicinal ingredient and hyaluronic acid and process for producing the same |
| US5811410A (en) * | 1989-09-21 | 1998-09-22 | Hyal Pharmaceutical Corporation | Method of administering of a hyaluronic acid and an NSAID to decrease side effects of the NSAID |
| US5817644A (en) * | 1991-07-03 | 1998-10-06 | Hyal Pharmaceutical Corporation | Targeting of dosages of medicine and therapeutic agents |
| WO1998043664A1 (en) * | 1997-04-01 | 1998-10-08 | Lg Chemical Limited | Sustained-release composition of drugs encapsulated in microparticles of hyaluronic acid |
| US5942498A (en) * | 1992-02-20 | 1999-08-24 | Hyal Pharmaceutical Corporation | Formulations containing hyaluronic acid |
| US5990095A (en) * | 1991-07-03 | 1999-11-23 | Hyal Pharmaceutical Corporation | Use of hyaluronic acid and forms to prevent arterial restenosis |
| US6022866A (en) * | 1991-07-03 | 2000-02-08 | Hyal Pharmaceutical Corporation | Use of hyaluronic acid and forms to prevent arterial restenosis |
| US6103704A (en) * | 1991-07-03 | 2000-08-15 | Hyal Pharmaceutical Corporation | Therapeutic methods using hyaluronic acid |
| US7091176B2 (en) | 1993-12-28 | 2006-08-15 | Allergan, Inc. | Methods for treating arthritis pain |
| US7276251B2 (en) | 1997-04-01 | 2007-10-02 | Lg Life Sciences, Ltd., Inc. | Sustained-release composition of drugs encapsulated in microparticles of hyaluronic acid |
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-
1988
- 1988-05-13 JP JP63116678A patent/JPH01287041A/en active Pending
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