JPS6136491B2 - - Google Patents
Info
- Publication number
- JPS6136491B2 JPS6136491B2 JP53073792A JP7379278A JPS6136491B2 JP S6136491 B2 JPS6136491 B2 JP S6136491B2 JP 53073792 A JP53073792 A JP 53073792A JP 7379278 A JP7379278 A JP 7379278A JP S6136491 B2 JPS6136491 B2 JP S6136491B2
- Authority
- JP
- Japan
- Prior art keywords
- nitroglycerin
- patch
- angina
- weight
- pharmaceutical composition
- 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.)
- Expired
Links
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims description 49
- 239000000006 Nitroglycerin Substances 0.000 claims description 48
- 229960003711 glyceryl trinitrate Drugs 0.000 claims description 48
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 6
- 229960000846 camphor Drugs 0.000 claims description 6
- 241000723346 Cinnamomum camphora Species 0.000 claims description 5
- 108010010803 Gelatin Proteins 0.000 claims description 5
- 229930008380 camphor Natural products 0.000 claims description 5
- 229920000159 gelatin Polymers 0.000 claims description 5
- 239000008273 gelatin Substances 0.000 claims description 5
- 235000019322 gelatine Nutrition 0.000 claims description 5
- 235000011852 gelatine desserts Nutrition 0.000 claims description 5
- 235000011187 glycerol Nutrition 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 2
- 150000001720 carbohydrates Chemical class 0.000 claims 1
- 206010002383 Angina Pectoris Diseases 0.000 description 27
- 238000004519 manufacturing process Methods 0.000 description 19
- 230000000694 effects Effects 0.000 description 9
- 230000017531 blood circulation Effects 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 230000000699 topical effect Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 6
- 229920003002 synthetic resin Polymers 0.000 description 6
- 239000000057 synthetic resin Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000006190 sub-lingual tablet Substances 0.000 description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000011888 foil Substances 0.000 description 4
- -1 Softeners Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000002075 main ingredient Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010040880 Skin irritation Diseases 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000004351 coronary vessel Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 239000003607 modifier Substances 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 231100000957 no side effect Toxicity 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000000123 paper Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 230000036556 skin irritation Effects 0.000 description 2
- 231100000475 skin irritation Toxicity 0.000 description 2
- 229940098466 sublingual tablet Drugs 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- WOEPIQOANYGRGK-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol propane-1,2,3-triol Chemical compound OCC(O)CO.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WOEPIQOANYGRGK-RJMJUYIDSA-N 0.000 description 1
- DMBSFYPSHNCYAR-RJMJUYIDSA-N 1,3-dinitrooxypropan-2-yl nitrate (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O DMBSFYPSHNCYAR-RJMJUYIDSA-N 0.000 description 1
- 208000019300 CLIPPERS Diseases 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 208000021930 chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids Diseases 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000352 effect on angina Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000011088 parchment paper Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Description
【発明の詳細な説明】
本発明はニトログリセリンを主成分とする外用
貼付剤に係る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an external patch containing nitroglycerin as a main ingredient.
ニトログリセリンは冠状血管拡張剤として有用
であり、狭心症の発作時にその抑制の目的で又は
発作予防を目的として汎用されている。ニトログ
リセリンは粘膜からの吸収性が良好であるため
に、狭心症発作の緊急抑制の場合には舌下投与法
が一般に使用され、又発作の予防を目的とする場
合には一般に徐放性製剤の形で経口的に服用され
腸管から徐々に吸収されるようになされる。 Nitroglycerin is useful as a coronary vasodilator and is widely used for the purpose of suppressing angina pectoris during attacks or for the purpose of preventing attacks. Because nitroglycerin is well absorbed through mucous membranes, sublingual administration is generally used for emergency control of angina attacks, and sustained-release administration is generally used for attack prevention. It is taken orally in the form of a preparation and is gradually absorbed through the intestinal tract.
舌下投与法は緊急時の発作抑制に関して有利な
方法ではあるが投与量、安全性等の観点から予防
法として適用する上で好適なものと言えず、又予
防を目的として投与される慣用の徐放性製剤は腸
又は胃内のPH、飲食状態等の種々のフアクタによ
り吸収度合が個人的に又は日時的に変化し易く、
従つて薬効の発現にバラツキがあり、このために
経口投与法が投与法として最適なものとも云い難
い。 Although sublingual administration is an advantageous method for suppressing seizures in emergencies, it cannot be said to be suitable for use as a prophylactic method from the viewpoint of dosage and safety. The degree of absorption of sustained-release preparations tends to vary from person to person or from time to time depending on various factors such as pH in the intestines or stomach, eating and drinking conditions, etc.
Therefore, there is variation in the expression of drug efficacy, and for this reason, it is difficult to say that oral administration is the optimal administration method.
一方、ニトログリセリンは粘膜から吸収される
のみならず、皮膚からも吸収されることが実証さ
れ、従つてこれを応用する軟膏製剤等も提案され
るに至つている。しかしながら、これらの製剤に
おいて主成分であるニトログリセリンが気散し易
いために軟膏製剤等を塗布した施用部位を硫酸紙
又は合成樹脂フイルム等により覆う必要性があり
且つ社会活動等を行なう場合には更にプラスター
等を用いて被覆材を定着させる必要性があり、従
つて使用上の便宜性に欠けるのみならず、吸収量
の制御が極めて困難であるために所要薬効を維持
することができないと謂う致命的な欠陥があり、
又安全性についても満足し得るものとは必ずしも
云い得ないのである。 On the other hand, it has been demonstrated that nitroglycerin is absorbed not only through the mucous membranes but also through the skin, and ointment formulations and the like that apply this have also been proposed. However, since the main ingredient in these preparations, nitroglycerin, easily diffuses, it is necessary to cover the application area with parchment paper or synthetic resin film, etc. when engaging in social activities, etc. Furthermore, it is necessary to fix the coating material using plaster, etc., which not only lacks convenience in use, but also makes it impossible to maintain the required medicinal efficacy because it is extremely difficult to control the amount absorbed. It has a fatal flaw,
Furthermore, safety cannot always be said to be satisfactory.
斯くて、本発明の主たる目的は、投与が極めて
簡便であり且つ吸収量の制御が容易なニトログリ
セリン製剤、殊にその外用貼付剤を提供すること
にある。 Therefore, the main object of the present invention is to provide a nitroglycerin preparation, particularly an external patch thereof, which is extremely easy to administer and whose absorption amount can be easily controlled.
本発明の附随的目的は、軟膏剤タイプのものよ
りも使用に際して簡便であり、使用感が良好であ
り、狭心症発作の予防乃至抑制効果が高く、然も
皮膚に対する刺戟性が低いニトログリセリン外用
貼付剤を提供することにある。 Ancillary objects of the present invention are to provide nitroglycerin which is easier to use than ointment-type products, has a good feeling of use, has a high preventive or suppressive effect on angina pectoris attacks, and has low skin irritation. The purpose of the present invention is to provide a patch for external use.
本発明によれば、上記の諸目的は、ニトログリ
セリン１−３重量％と、糖類16−20重量％と、ニ
トログリセリン10−35重量％と、ゼラチン６−15
重量％と、カンフル0.3−１重量％と、水10−40
重量％とを含有する製剤組成物が担体により保持
されていることを特徴とする、ニトログリセリン
外用貼付剤により達成される。 According to the invention, the above objects are achieved by combining 1-3% by weight of nitroglycerin, 16-20% by weight of sugars, 10-35% by weight of nitroglycerin and 6-15% by weight of gelatin.
wt%, camphor 0.3-1 wt%, water 10-40
% by weight is carried by a carrier.
本発明によるニトログリセリン外用貼付剤の製
剤組成物において、糖類はニトログリセリンの発
火性及び揮発性を減少させるために配合され、グ
リセリンやゼラチンは基剤を構成するために配合
され、カンフルはニトログリセリンの吸収調整剤
として配合される。糖類としては乳糖を用いるの
が好ましいが、デンプン、サイクロデキストリン
等を使用することもできる。勿論、製剤組成物に
は、必要に応じて貼着剤、貼着調整剤、充填剤、
軟化剤、安定化剤、殺菌消毒剤、抗アレルギー剤
等を配合することができる。製剤組成物が塗布接
合されて保持される担体としては比較的薄手であ
り可撓性を有するもの例えば布体、紙葉、合成樹
脂フイルム、アルミニウム箔等又はこれらの複合
体を例示することができる。 In the pharmaceutical composition of the nitroglycerin topical patch according to the present invention, sugars are blended to reduce the ignitability and volatility of nitroglycerin, glycerin and gelatin are blended to constitute the base, and camphor is blended to reduce the ignitability and volatility of nitroglycerin. It is formulated as an absorption modifier. As the sugar, it is preferable to use lactose, but starch, cyclodextrin, etc. can also be used. Of course, the pharmaceutical composition may contain adhesives, adhesive modifiers, fillers,
Softeners, stabilizers, sterilizing agents, anti-allergic agents, etc. can be added. Examples of carriers on which the pharmaceutical composition is applied and bonded include relatively thin and flexible carriers such as cloth, paper sheets, synthetic resin films, aluminum foils, etc., or composites thereof. .
本発明によるニトログリセリン外用貼付剤にお
いて、主剤であるニトログリセリンの含有量は、
この貼付剤を狭心症の発作時における制御目的で
用いるのか、或いは発作の予防目的で用いるのか
に依存して変化するが、本発明はこれらの何れの
目的にも供し得る貼付剤を企図しており、従つて
製剤組成物が担体上に均斉な厚さで塗布接合され
て貼付剤を構成している場合に、表面積54cm2（６
×９cm）の担体上に保持される製剤組成物がニト
ログリセリンを少なくとも15mg含有しているよう
になされる。 In the nitroglycerin topical patch according to the present invention, the content of nitroglycerin as the main ingredient is as follows:
Although it depends on whether this patch is used for the purpose of controlling an attack of angina pectoris or for the purpose of preventing an attack, the present invention contemplates a patch that can be used for either of these purposes. Therefore, when the pharmaceutical composition is coated on a carrier with a uniform thickness to form a patch, the surface area is 54 cm 2 (6
x 9 cm) carrier contains at least 15 mg of nitroglycerin.
尚、本発明によるニトログリセリン外用貼付剤
は大面積を有する担体に製剤組成物が塗布接合さ
れて製造されるが、気密包装に先立ち截断され、
斯くて患者の疾患程度、使用経験、貼付部位、体
質等の個々のフアクタを考慮して貼付面積を、延
いてはニトログリセリンの投与量を調整し得るよ
うになされる。 The nitroglycerin topical patch according to the present invention is manufactured by coating and bonding the pharmaceutical composition onto a carrier having a large area, but it is cut into pieces before being airtightly packaged.
In this way, the application area and, by extension, the dosage of nitroglycerin can be adjusted in consideration of individual factors such as the patient's degree of disease, usage experience, application site, and constitution.
次に製造例、比較製造例、薬効薬理試験例、臨
床試験例、使用感等の官能調査に関連して本発明
を更に詳細に説明する。 Next, the present invention will be explained in more detail in connection with production examples, comparative production examples, medicinal efficacy pharmacological test examples, clinical test examples, and sensory investigations such as feeling of use.
製造例
(a) アルミニウム箔と、ポリエチレン等の熱可塑
性合成樹脂フイルムと、リンタ材（スフリン
タ、ナイロンリンタ、ポリエステルリンタ等で
あることができる）層とを積層し、加熱接合し
て積層状の担体を製造した。Production example (a) Aluminum foil, a thermoplastic synthetic resin film such as polyethylene, and a layer of linter material (which can be sufflinter, nylon linter, polyester linter, etc.) are laminated and heated and bonded to form a laminated carrier. was manufactured.
(b) 1.6ｇのポリアクリル酸ナトリウムと、0.6ｇ
のカーボポール90とを混和し、次いで別途調製
された６ｇのゼラチンと、３ｇのTween80
と、31ｇのグリセリンと、適量の日本薬局方精
製水との混合物に添加し、更に20ｇのニトログ
リセリン（乳糖）10倍散と0.4ｇのdl−カンフ
ルとを添加して全量100ｇの製剤組成物を調製
した。(b) 1.6g of sodium polyacrylate and 0.6g
of Carbopol 90, then 6 g of gelatin prepared separately and 3 g of Tween 80.
was added to a mixture of 31 g of glycerin and an appropriate amount of Japanese Pharmacopoeia purified water, and further 20 g of nitroglycerin (lactose) 10-fold powder and 0.4 g of DL-camphor were added to form a pharmaceutical composition with a total amount of 100 g. was prepared.
この製剤組成物を、上記の(a)項に記載の方法で
得られた担体上に数mmの厚さとなるように均斉に
塗布して接合させれば、所望のニトログリセリン
外用貼付剤が得られる。この貼付剤は、既述の通
り54cm2（６×９cm）当り少なくとも15mgのニトロ
グリセリンを含有している必要性があるが、これ
は上記製剤組成物の塗布厚さを約２mm又はそれ以
上に設定することにより行なうことができる。 The desired nitroglycerin topical patch can be obtained by uniformly coating and bonding this pharmaceutical composition onto the carrier obtained by the method described in (a) above to a thickness of several mm. It will be done. This patch must contain at least 15 mg of nitroglycerin per 54 cm 2 (6 x 9 cm), as described above, which increases the coating thickness of the pharmaceutical composition to about 2 mm or more. This can be done by setting.
製造されたこの貼付剤の包装に際しては、先
ず、製剤組成物層の外面に防散用台紙（これは自
体慣用のもの、例えばセロフアン、合成樹脂処理
した紙葉、気密性を有する合成樹脂フイルム、ア
ルミニウム箔等であることができる）が圧着さ
れ、次いで所定の寸法に截断され、その後に個々
に又は所定枚数宛アルミニウム箔製の又はポリ塩
化ビニール等の気密性合成樹脂フイルム製の包装
袋内に装填される。 When packaging the produced patch, first, a scattering mount is placed on the outer surface of the pharmaceutical composition layer (this is a conventional material such as cellophane, paper sheets treated with synthetic resin, airtight synthetic resin film, etc.). (can be aluminum foil, etc.) are crimped, then cut to predetermined dimensions, and then individually or in predetermined numbers in packaging bags made of aluminum foil or airtight synthetic resin film such as polyvinyl chloride. loaded.
比較製造例
３ｇのワセリンと、35ｇのラノリンと、２ｇの
Tween80とを混和し、次いで別途調製された13
ｇのゼラチンと、13ｇのグリセリンと、適量の日
本薬局方精製水との混合物を上記の混和物に添加
し、更に20ｇのグリセリン（乳糖）10倍散を添加
して全量100ｇの製剤組成物を調製した。Comparative manufacturing example: 3g of petrolatum, 35g of lanolin, 2g of
Mix with Tween80 and then separately prepared 13
A mixture of 1 g of gelatin, 13 g of glycerin, and an appropriate amount of Japanese Pharmacopoeia purified water was added to the above mixture, and 20 g of glycerin (lactose) 10-fold powder was added to prepare a total amount of 100 g of a pharmaceutical composition. Prepared.
この製剤組成物を、製造例１と同様にして、担
体上に塗布し接合させて比較試験用のニトログリ
セリン外用貼付剤を得た。 This pharmaceutical composition was applied onto a carrier and bonded in the same manner as in Production Example 1 to obtain a nitroglycerin external patch for comparative testing.
薬効薬理試験例 １
本発明が対象としているニトログリセリン外用
貼付剤における吸収排泄はニトログリセリンの代
謝が早いために一般的なRI測定法を採用してニ
トログリセリンの生体内動態を直接的に観察する
ことは不可能である。従つて、犬の冠状動脈狭搾
による実験的狭心症モデルを用いて心筋心電図、
冠血流量、大動脈血流量、心拍出量を測定し、こ
れによつてニトログリセリンの狭心症抑制作用を
誌験した。即ち正常状態では毎分30mlを示した冠
血流量を狭搾きにより毎分15mlにコントロールし
て以下の実験を行なつた。Pharmaceutical efficacy pharmacology test example 1 Since the absorption and excretion of nitroglycerin in the topical nitroglycerin patch targeted by the present invention is rapidly metabolized, the in-vivo dynamics of nitroglycerin are directly observed using a general RI measurement method. That is impossible. Therefore, using an experimental angina model caused by canine coronary artery constriction, myocardial electrocardiogram,
Coronary blood flow, aortic blood flow, and cardiac output were measured, and the angina suppressive effect of nitroglycerin was investigated. That is, the following experiment was conducted by controlling the coronary blood flow, which was 30 ml per minute under normal conditions, to 15 ml per minute by narrow squeezing.
先ず、狭搾状態でペーシングをかけた処、心筋
心電図上には狭心症の指標となるST変化が生
じ、同時に冠血流量も若干増大した。次に、比較
製造例による貼付剤を心臓表面冠状動脈下向枝流
域に貼付した処15分後より顕著な冠血流量の増大
を示し、正常時に略匹敵する冠血流量の改善が見
られた。更に、貼付剤の貼付から15分間経過後に
ペーシングをかけた処、無処置の対照（コントロ
ール）に見られるような心電図のST変化は認め
られなかつた。この作用は30分後にも観察された
が、60分経過後には消失していた。 First, when pacing was applied in a constricted state, ST changes, an indicator of angina pectoris, occurred on the myocardial electrocardiogram, and at the same time, coronary blood flow increased slightly. Next, 15 minutes after applying the patch according to the comparative manufacturing example to the descending branch area of the coronary artery on the surface of the heart, a significant increase in coronary blood flow was observed, and an improvement in coronary blood flow comparable to normal blood flow was observed. . Furthermore, when pacing was applied 15 minutes after application of the patch, no ST change in the electrocardiogram was observed as seen in the untreated control. This effect was observed even after 30 minutes, but disappeared after 60 minutes.
一方、製造例に記載の方法により得た、カンフ
ル含有ニトログリセリン外用貼付剤を用いて上記
と同様な実験を行なつた処、貼付の５分後より顕
著な冠血流量の増大を示した。貼付剤の貼付から
５、15、30及び60分経過後にペーシングをそれぞ
れかけた処、ST変化の抑制は５分後から30分ま
で観察されたが、60分経過後には消失していた。 On the other hand, when an experiment similar to the above was conducted using a camphor-containing nitroglycerin topical patch prepared by the method described in the Production Example, a significant increase in coronary blood flow was observed 5 minutes after application. When pacing was applied 5, 15, 30, and 60 minutes after application of the patch, suppression of ST changes was observed from 5 minutes to 30 minutes, but disappeared after 60 minutes.
上記の結果から、カンフルを配合することによ
りニトログリセリンの吸収が調整されその薬効発
現が速やかとなることが判明した。 From the above results, it was found that by incorporating camphor, the absorption of nitroglycerin was adjusted and its medicinal efficacy was quickly expressed.
薬効薬理試験例 ２
体重300±12ｇの雄性Wister系ラツトを実験物
とし、胸部を体毛をバリカンで刈り、刈取つた部
分を除毛剤で５分間処理した後に24時間個別に飼
育した。Pharmacology Test Example 2 Male Wistar rats weighing 300±12 g were used as experimental subjects. Hair on the chest was shaved with clippers, and the clipped area was treated with a hair remover for 5 minutes before being housed individually for 24 hours.
その後、ラツトの除毛胸部に、製造例及び比較
製造例により得られた外用貼付剤を貼付し（製剤
組成物の重量が50mgであつて、ニトログリセリン
として１mg／匹）、経時的に尾部を切断して0.8
ml／回宛採血し、Peter S.K.Yap等〔“J.Pharm.
Soc.”67、584（1978）〕の方法により、その血漿
0.2mlに硝酸銀を10μｌ添加し、ｎ−ヘキサン0.2
mlで６回抽出し、合併抽出液中の抽出液を留去
し、内部標準物質として硝酸イソソルビトールを
４μ４／４μｌ添加し、その内の２−３μｌをガ
スクロマトグラフイーにかけて検量線からニトロ
グリセリンの血漿中濃度を定量した。 Thereafter, the external patch obtained in the Production Example and Comparative Production Example was applied to the hair-free chest of the rat (the weight of the formulation composition was 50 mg, and the amount of nitroglycerin was 1 mg/mouse), and the tail was removed over time. Cut to 0.8
Blood was drawn per ml, and Peter SKYap et al. [“J.Pharm.
Soc.” 67 , 584 (1978)].
Add 10μl of silver nitrate to 0.2ml and add 0.2ml of n-hexane.
ml 6 times, the extract in the combined extract was distilled off, 4 μ 4 /4 μl of isosorbitol nitrate was added as an internal standard substance, and 2-3 μl of it was subjected to gas chromatography to determine nitroglycerin from the calibration curve. The plasma concentration of was quantified.
結果は添付図面のグラフに示される通りであ
り、製造例による貼付剤では15分以内に最高濃度
である12μｇ/mlに達し、一方比較製造例による
貼付剤では約30分後に最高濃度に達し、その後は
何れの場合にも比較的濃度の減少することが判明
した。 The results are as shown in the graph of the attached drawing, and the patch according to the production example reached the maximum concentration of 12 μg/ml within 15 minutes, while the patch according to the comparative production example reached the maximum concentration after about 30 minutes. After that, it was found that the concentration decreased relatively in all cases.
臨床試験例
(a) 労作性狭心症の治療
１週間に狭心症発作が延べ16回発生し、発作
においてその抑制のために延べ20錠のニトログ
リセリン舌下錠（１錠当りニトログリセリン
0.3mgを含有）を必要としていた45才の男性患
者に、製造例に記載の貼付剤（１枚当り、ニト
ログリセリンを15mg含有）を１−２回／日（毎
回１枚）胸部に貼付した処、狭心症発作は６
回／日に減少し、ニトログリセリン舌下錠の使
用量も延べ４錠に減少した。Clinical trial example (a) Treatment of exertional angina A total of 16 angina attacks occurred in one week, and a total of 20 sublingual nitroglycerin tablets (each tablet contains nitroglycerin
The patch described in the manufacturing example (each patch contains 15 mg of nitroglycerin) was applied to the chest 1-2 times/day (one patch each time) to a 45-year-old male patient who needed nitroglycerin (containing 0.3 mg). angina pectoris attack is 6
times/day, and the amount of nitroglycerin sublingual tablets used decreased to a total of 4 tablets.
貼付剤の使用を更に継続した処（毎日１
回）、２週間後には発作が生起しなくなり、ニ
トログリセリン舌下錠投与の必要性はなくなつ
た。 Continued use of the patch (1 day per day)
After 2 weeks, the seizures stopped occurring, and there was no need to administer nitroglycerin sublingual tablets.
尚、貼付剤の連用にも拘らず、頭痛等の副作
用の発生は認められなかつた。 In addition, despite continuous use of the patch, no side effects such as headache were observed.
(b) 異型労作性狭心症の治療
約３ケ月前から狭心症発作が起り始め、現在
では夜間や歩行時等に４−５回／日の労作性狭
心痛が生起するようになつた62才の男性患者
に、製造例に記載の貼付剤（１枚当り、ニトロ
グリセリンを15mg含有）を３回／日貼付した
（毎回１枚）。継続して貼付させた処、夜間の狭
心痛発生は消失し、労作性狭心痛の発生回数も
減少し、痛みの程度に著しい弱化が認められ
た。(b) Treatment of atypical exertional angina The patient started having angina attacks about 3 months ago, and is now experiencing exertional angina 4-5 times a day at night or when walking. The patch described in the manufacturing example (containing 15 mg of nitroglycerin per patch) was applied three times/day to a 62-year-old male patient (one patch each time). With continued application, the occurrence of nighttime angina disappeared, the frequency of exertional angina decreased, and a significant decrease in the degree of pain was observed.
(c) 異型狭心型の治療
約３年前に毎日のように夜間狭心痛を経験し
たことのある50才の男性に、夜間殊に午前２時
から４時にかけて発生する安静狭心痛が再発し
た。この患者に対し、製造例に記載の貼付剤
（１枚当り、ニトログリセリンを15mg含有）を
就寝前（午後10時）に１枚貼付させた処、前記
の安静狭心痛の発生は完全に消失した。(c) Treatment of atypical angina A 50-year-old man who had experienced nocturnal angina almost every day about 3 years ago was diagnosed with recurrent rest angina that occurred at night, especially between 2:00 a.m. and 4:00 a.m. did. When this patient was given one patch (containing 15 mg of nitroglycerin per patch) described in the manufacturing example before going to bed (10 p.m.), the occurrence of rest angina completely disappeared. did.
本治療例は本発明による貼付剤の薬効が長時
間にわたつて持続することを示すものである。 This treatment example shows that the efficacy of the patch according to the present invention is sustained over a long period of time.
(d) 労作性狭心症の予防
労作による狭心痛を生起し易く、この狭心痛
発生時にイソソルバイドジニトレートニトログ
リセリン舌下錠の投与が有効であつた56才の男
性に、製造例に記載の貼付剤（１枚当り、ニト
ログリセリンを15mg含有）を１枚貼付し、１時
間経過後に運動負荷試験を実施した処、狭心痛
は何等発生しなかつた。(d) Prevention of exertional angina A 56-year-old man who was prone to anginal pain due to exertion, and for whom administration of isosorbide dinitrate nitroglycerin sublingual tablets was effective at the time of anginal pain, was given a manufacturing example. When one patch described above (containing 15 mg of nitroglycerin per patch) was applied and an exercise stress test was conducted one hour later, no anginal pain occurred.
(e) 労作性狭心症の治療
歩行時等に狭心痛が発生するために１週間に
１−２錠のニトログリセリン舌下錠を常用して
い55才の男性に対し、狭心症発生時に、舌下錠
に代えて製造例に記載の貼付剤（１枚当り、ニ
トログリセリンを15mg含有）を１枚貼付した
処、効果の発現は舌下錠と比較する場合に若干
遅延するが、発現後は長時間にわたつて効果の
持続することが認められた。その後の狭心症発
作時にニトログリセリンを22.5mg含有する貼付
剤を用いた処、その効果は12時間程度持続する
ことが判明した。(e) Treatment of exertional angina A 55-year-old man who regularly takes 1 to 2 sublingual nitroglycerin tablets per week due to angina pain when walking etc. was treated when angina occurred. When one patch described in the manufacturing example (containing 15 mg of nitroglycerin per patch) was applied instead of the sublingual tablet, the onset of effect was slightly delayed compared to the sublingual tablet, but Afterwards, it was observed that the effect lasted for a long time. When a patch containing 22.5 mg of nitroglycerin was used during a subsequent angina attack, it was found that the effect lasted for about 12 hours.
尚、貼付剤の使用中に頭痛やめまい等の副作
用発生は何等認められなかつた。 Incidentally, no side effects such as headache or dizziness were observed during use of the patch.
使用感、副作用等に関する官能調査
20名の健常人から構成されるパネルにおいて、
各パネラーの背部に、製造例に記載の貼付剤１枚
（６×９cm、ニトログリセリンを1.5mg含有）を貼
付し、６時間経過後に剥離して貼付感及び局所的
副作用（痛痒、湿疹、皮膚炎の発生等）の有無に
つきアンケート調査を実施した処、副作用を訴え
る者はなく、貼付時に異和感を感せず且つ貼付中
及び剥離後において爽快感がある旨全パネラーは
表明した。Sensory survey regarding usability, side effects, etc. In a panel consisting of 20 healthy people,
One patch (6 x 9 cm, containing 1.5 mg of nitroglycerin) described in the manufacturing example was applied to the back of each panelist, and after 6 hours, it was peeled off to determine the feeling of the patch and local side effects (itch, eczema, skin irritation). A questionnaire survey was conducted to find out whether there was any occurrence of flames, etc.), and no one complained of side effects, and all panelists stated that they did not feel any discomfort when applying the product, and that they felt refreshed during application and after peeling it off.
添付図面は製造例及び比較製造例に記載の方法
により調製されたニトログリセリン外用貼付剤を
ラツトに貼付した場合の、ニトログリセリンの血
漿中濃度と経過時間との関係を示すグラフであ
る。
The accompanying drawing is a graph showing the relationship between the plasma concentration of nitroglycerin and the elapsed time when a topical nitroglycerin patch prepared by the method described in the Production Examples and Comparative Production Examples is applied to rats.
Claims (1)
20重量％と、グリセリン10−35重量％と、ゼラチ
ン６−15重量％と、カンフル0.3−１重量％と、
水10−40重量％とを含有する製剤組成物が担体に
より保持されていることを特徴とする、ニトログ
リセリン外用貼付剤。 ２ 糖類が乳糖であることを特徴とする、特許請
求の範囲第１項に記載のニトログリセリン外用貼
付剤。 ３ 担体の表面積が54cm2（６×９cm）であり、こ
の担体上に均斉な厚さで塗布接合されている製剤
組成物のニトログリセリン含有量が少なくとも15
mgであることを特徴とするる、特許請求の範囲第
１項に記載のニトログリセリン外用貼付剤。[Claims] 1. 1-3% by weight of nitroglycerin and 16-
20% by weight, 10-35% by weight of glycerin, 6-15% by weight of gelatin, and 0.3-1% by weight of camphor.
1. A nitroglycerin patch for external use, characterized in that a pharmaceutical composition containing 10-40% by weight of water is supported by a carrier. 2. The nitroglycerin patch for external use according to claim 1, wherein the saccharide is lactose. 3 The surface area of the carrier is 54 cm 2 (6 x 9 cm), and the nitroglycerin content of the pharmaceutical composition coated on the carrier with a uniform thickness is at least 15
The nitroglycerin external patch according to claim 1, characterized in that the nitroglycerin patch is mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7379278A JPS552604A (en) | 1978-06-20 | 1978-06-20 | Patch agent consisting mainly of nitroglycerin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7379278A JPS552604A (en) | 1978-06-20 | 1978-06-20 | Patch agent consisting mainly of nitroglycerin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS552604A JPS552604A (en) | 1980-01-10 |
| JPS6136491B2 true JPS6136491B2 (en) | 1986-08-19 |
Family
ID=13528384
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7379278A Granted JPS552604A (en) | 1978-06-20 | 1978-06-20 | Patch agent consisting mainly of nitroglycerin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS552604A (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1163561A (en) * | 1979-11-06 | 1984-03-13 | Cyril Boroda | Preparation containing nitroglycerine and optionally other medicaments and preparation thereof |
| JPS56123912A (en) * | 1980-03-05 | 1981-09-29 | Nitto Electric Ind Co Ltd | Drug-containing tape preparation |
| JPH03246219A (en) * | 1980-03-25 | 1991-11-01 | Nippon Kayaku Co Ltd | Pressure sensitive tacky tape or sheet containing nitroglycerin |
| JPS56133381A (en) * | 1980-03-25 | 1981-10-19 | Nippon Kayaku Co Ltd | Pressure-sensitive adhesive tape or sheet containing nitroglycerin |
| JPS577412A (en) * | 1980-06-14 | 1982-01-14 | Nitto Electric Ind Co Ltd | Plaster |
| JPS5777617A (en) * | 1980-10-20 | 1982-05-15 | Nichiban Co Ltd | Plaster for cardiac disease |
| JPS5843368B2 (en) * | 1980-10-30 | 1983-09-27 | 日東電工株式会社 | Anti-inflammatory analgesic patch |
| JPS57116011A (en) * | 1981-01-08 | 1982-07-19 | Nitto Electric Ind Co Ltd | Pharmaceutical preparation |
| JPS57183714A (en) * | 1981-05-01 | 1982-11-12 | Nitto Electric Ind Co Ltd | Medicinal pharmaceutical |
| JPS61251618A (en) * | 1985-04-30 | 1986-11-08 | Nitto Electric Ind Co Ltd | Drug material for external use |
| JPH0696529B2 (en) * | 1987-03-31 | 1994-11-30 | 積水化学工業株式会社 | Nitroglycerin patch and method for producing the same |
| JPS63246326A (en) * | 1987-11-07 | 1988-10-13 | Nippon Kayaku Co Ltd | Production of pressure-sensitive tape or sheet containing nitroglycerin |
| JPH07116032B2 (en) * | 1990-04-06 | 1995-12-13 | 積水化学工業株式会社 | Nitroglycerin patch |
| DE19701949A1 (en) * | 1997-01-13 | 1998-07-16 | Jenapharm Gmbh | Transdermal therapeutic system |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4858117A (en) * | 1971-11-22 | 1973-08-15 | ||
| JPS4950127A (en) * | 1972-09-22 | 1974-05-15 | ||
| JPS52143223A (en) * | 1976-05-25 | 1977-11-29 | Watanabe Yakuhin Kogyo Kk | Pap gent |
| JPS5350320A (en) * | 1976-10-14 | 1978-05-08 | Watanabe Yakuhin Kogyo Kk | Hydrophylic plaster |
-
1978
- 1978-06-20 JP JP7379278A patent/JPS552604A/en active Granted
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4858117A (en) * | 1971-11-22 | 1973-08-15 | ||
| JPS4950127A (en) * | 1972-09-22 | 1974-05-15 | ||
| JPS52143223A (en) * | 1976-05-25 | 1977-11-29 | Watanabe Yakuhin Kogyo Kk | Pap gent |
| JPS5350320A (en) * | 1976-10-14 | 1978-05-08 | Watanabe Yakuhin Kogyo Kk | Hydrophylic plaster |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS552604A (en) | 1980-01-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4704119A (en) | Method comprising transdermal and buccal treatment of angina | |
| Dixit et al. | Oral strip technology: Overview and future potential | |
| JPS6136491B2 (en) | ||
| KR100267359B1 (en) | Transdermal administration system containing acetylsalicylic acid for antithrombotic therapy | |
| US4696821A (en) | Transdermal delivery system for administration of nitroglycerin | |
| FR2567758A1 (en) | THINAPEUTIC COMPOSITIONS BASED ON GINKGOLIDES FOR THE TREATMENT OR PREVENTION OF DISEASES CAUSED BY ACETHER OF PLATELET ACTIVATION FACTOR (PAF-ACETHER) | |
| JPH09504810A (en) | Water-soluble pressure sensitive mucoadhesive | |
| CA2056653A1 (en) | Preparation for transdermal drug administration | |
| JPH0541602B2 (en) | ||
| JP2000512996A (en) | Preventive and therapeutic measures for skin sensitization and irritation | |
| JPS58213709A (en) | Application agent for gum mucosa | |
| WO2012009438A2 (en) | Anti-appetite adhesive compositions | |
| WO2012090194A2 (en) | Compositions and methods for treating a skin disorder | |
| KR20170139979A (en) | Oral sealing wrap having extendable property | |
| Jaiswal | Oral strip technology: A review | |
| JP2001512428A (en) | Extendable transdermal therapeutic system | |
| WO2006042928A1 (en) | Composition for preventing or treating stress, especially chronic and permanent bursts of stress | |
| JPH01230514A (en) | Aerosol type patch external use | |
| JP2007512270A (en) | Oral formulations of deoxypeganine and their use | |
| JP3799502B2 (en) | Transdermal administration system containing acetylsalicylic acid for antithrombotic treatment and cancer prevention | |
| JP2001505222A (en) | Topical formulation for introducing peptide drugs into organisms | |
| JPH0335285B2 (en) | ||
| JPS60214732A (en) | Application agent for external use | |
| JPS6115829A (en) | Sustained release nifedipine pharmaceutical for application to oral mucosa | |
| WO2009150324A1 (en) | Magnesium system and use thereof in the cosmetics industry |