CN104147002B - Indapamide bisoprolol transdermal skin patches and preparation method thereof - Google Patents
Indapamide bisoprolol transdermal skin patches and preparation method thereof Download PDFInfo
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- CN104147002B CN104147002B CN201410422382.7A CN201410422382A CN104147002B CN 104147002 B CN104147002 B CN 104147002B CN 201410422382 A CN201410422382 A CN 201410422382A CN 104147002 B CN104147002 B CN 104147002B
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- CN
- China
- Prior art keywords
- bisoprolol
- indapamide
- skin patches
- transdermal skin
- sensitive adhesive
- Prior art date
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- Expired - Fee Related
Links
- 229960002781 bisoprolol Drugs 0.000 title claims abstract description 124
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 title claims abstract description 119
- 229960004569 indapamide Drugs 0.000 title claims abstract description 84
- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 239000007933 dermal patch Substances 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 50
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 25
- 239000010410 layer Substances 0.000 claims abstract description 23
- 239000003513 alkali Substances 0.000 claims abstract description 22
- 239000003655 absorption accelerator Substances 0.000 claims abstract description 13
- 230000001464 adherent effect Effects 0.000 claims abstract description 4
- -1 bisoprolol organic acid ion Chemical class 0.000 claims description 30
- 239000000463 material Substances 0.000 claims description 27
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 25
- 235000002906 tartaric acid Nutrition 0.000 claims description 25
- 239000011975 tartaric acid Substances 0.000 claims description 25
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims description 22
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 20
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical group CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 claims description 20
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 12
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 11
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 11
- 229940041616 menthol Drugs 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 8
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 8
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 8
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 8
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000005642 Oleic acid Substances 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 8
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 150000003505 terpenes Chemical class 0.000 claims description 6
- 235000007586 terpenes Nutrition 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 5
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 5
- 150000002500 ions Chemical class 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 239000011976 maleic acid Substances 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- RZPZLFIUFMNCLY-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy]propan-2-ol Chemical compound OC(=O)\C=C\C(O)=O.CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 RZPZLFIUFMNCLY-WLHGVMLRSA-N 0.000 claims description 4
- 241001597008 Nomeidae Species 0.000 claims description 4
- 229920002367 Polyisobutene Polymers 0.000 claims description 4
- 229960005400 bisoprolol fumarate Drugs 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229920000058 polyacrylate Polymers 0.000 claims description 4
- 229920001296 polysiloxane Polymers 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 235000013372 meat Nutrition 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims 5
- 230000002745 absorbent Effects 0.000 claims 2
- 239000002250 absorbent Substances 0.000 claims 2
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000001360 synchronised effect Effects 0.000 abstract description 4
- 239000004745 nonwoven fabric Substances 0.000 description 22
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000035699 permeability Effects 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000013019 agitation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000003276 anti-hypertensive effect Effects 0.000 description 3
- 230000002354 daily effect Effects 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 229940096978 oral tablet Drugs 0.000 description 2
- 239000007935 oral tablet Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 229940097420 Diuretic Drugs 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940121792 Thiazide diuretic Drugs 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229940041794 bisoprolol oral tablet Drugs 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, relate to indapamide bisoprolol transdermal skin patches and preparation method thereof.Described indapamide bisoprolol transdermal skin patches is made up of backing layer, medicine carrying pressure-sensitive adhesive layer and adherent layer；Medicine carrying pressure-sensitive adhesive layer includes that indapamide, bisoprolol free alkali or its organic acid ion are to complex, pressure sensitive adhesive, transdermal absorption accelerator.Wherein indapamide, bisoprolol free alkali or its organic acid ion dose total to complex accounts for the 0.5wt% ~ 5.5wt% of medicine carrying pressure-sensitive adhesive layer gross weight, wherein indopamide, bisoprolol free alkali or its organic acid ion are 0.5:1 ~ 2:1 to the molar ratio of complex, the present invention is capable of in transdermal skin patches passing through indapamide and bisoprolol percutaneous the two-ways regulation of ability, it is achieved that two medicines pass through from the synchronized of transdermal skin patches.
Description
Technical field:
The invention belongs to pharmaceutical technology field, relate to indapamide bisoprolol transdermal skin patches and preparation method thereof.
Background technology:
In the clinical treatment of hypertension, at least the patient of 75% needs to use therapeutic alliance, to reach target blood pressure
Value.Hypertension therapeutic alliance is made up of the medicine with different Hypotensive Mechanism, generally has preferable blood pressure lowering to imitate than single therapy
Really.Due to this reason, market occurs in that antihypertensive formulation miscellaneous.In view of hypertension is a kind of chronic disease, patient's
Medication compliance is particularly important.Therefore, a kind of existing preferable antihypertensive effect of preparation, can improve again the percutaneous of patient medication compliance
Patch, is a preferable selection.
Indapamide, a kind of thiazide diuretic, the first-line drug of hypertension therapeutic it is defined as by JNC VIII.Bisoprolol,
A kind of high selectivity β1receptorblocker, is widely used in hypertension therapeutic for a long time.Diuretic is combined with beta-blocker,
It is identified as rational drug regimen, i.e. can increase antihypertensive effect, do not produce extra side effect simultaneously.Meanwhile, a kind of this
The oral tablet trade name of type(comprising hydrochlorothiazide and bisoprolol) lists, also demonstrates this type of combination
Reasonability.
Generally before preparing transdermal skin patches, must first consider component drug desired percutaneous transit dose.Clinical indapamide
The daily dose of oral tablet is 2.5mg, bioavailability approximation 100%.The clinical daily dose of bisoprolol oral tablet is
2.5mg-5mg, bioavailability is more than 80%.Owing to indapamide and the oral daily dose of bisoprolol and bioavailability are equal
Very much like, it means that every day is roughly equal by indapamide and the bisoprolol amount of needed by human body.Therefore, two medicines in patch
The percutaneous transit dose interior at 24 hours also should be equal.But, it is true that the bisoprolol accumulative percutaneous transit dose of 24 hours is Yin
Reach about 16 times of handkerchief amine.So, need energy Effective Regulation indapamide and the bisoprolol percutaneous method through ability badly, to reach
Synchronized from patch of two medicines passes through.
At present, change medicament contg or use release-controlled film is that the regulating drug percutaneous that transdermal delivery system two kinds is conventional passes through
The method of ability.The former is easy to implement, and is also applied for pressure sensitive adhesive decentralized transdermal skin patches.Generally increase drug loading and can improve medicine
Thing percutaneous in patch passes through ability, reduces drug loading and can reduce the percutaneous of medicine significantly through ability.But, this
Method has certain limitation, can not be suitable for all situations.This is because, increase drug loading excessively and patch Chinese medicine can be made to analyse
Go out crystallization, and reduce drug loading inadequately and can cause patch Chinese medicine dosage exhaustion along with using time lengthening.
The percutaneous two kind medicament adjusting different through ability are consistent, and most straightforward approach is just to increase through ability relatively
The percutaneous permeability of weak medicine, as increase indapamide through ability so that it is with bisoprolol through ability equal.So
And, all the time, be difficult to find a kind of can a kind of medicine of special increase through ability to another drug percutaneous permeability
Accelerator without impact.
Passing through capacity adjustment method owing to lacking gratifying drug percutaneous, this hinders many transdermal skin patches undoubtedly
Research and development.Excellent particularly with those pharmacology synergy, but drug percutaneous is difficult to the medicine of regulation through ability, including the application
In indapamide and bisoprolol.
Summary of the invention:
It is an object of the invention to provide the preparation of indapamide bisoprolol transdermal skin patches and drug percutaneous thereof through ability
The method of two-ways regulation, passes through from the synchronized of transdermal skin patches realizing indapamide and bisoprolol.
The present invention is achieved through the following technical solutions:
First synthesis bisoprolol and the ion-pair complexes of different organic acids, to substitute bisoprolol free alkali, thus
Reduce the percutaneous of bisoprolol through ability so that it is suitable through ability with the percutaneous of indapamide.Afterwards, employing chemically assists in
Agent increases the percutaneous of indapamide and bisoprolol through ability simultaneously.
Indapamide bisoprolol transdermal skin patches of the present invention is by backing layer, medicine carrying pressure-sensitive adhesive layer and adherent layer structure
Become；Medicine carrying pressure-sensitive adhesive layer includes that indapamide, bisoprolol free alkali or its organic acid ion are to complex, pressure sensitive adhesive, percutaneous
Absorption enhancer.Wherein to account for medicine carrying pressure-sensitive for indapamide, bisoprolol free alkali or its organic acid ion dose total to complex
0.5wt%～5.5wt% of glue-line gross weight, wherein indopamide, bisoprolol free alkali or its organic acid ion are to compound
The molar ratio of thing is 0.5:1～2:1, preferably 1:1.
The free alkali of bisoprolol is prepared via a method which: titrate fumaric acid peso with the aqueous solution of 20% sodium carbonate
The aqueous solution of Luo Er, to no longer there being oily liquids to produce, then extracts it with suitable single or mixed organic solvents, de-
After water, evaporation of organic solvent is drying to obtain.Organic solvent used can be aliphatic alcohols, ethers, alkanes, alkyl halide hydro carbons and
Fatty acid ester.Wherein preferred alkanes, alkyl halide hydro carbons and fatty acid ester.
Described bisoprolol organic acid ion is the pharmaceutically acceptable organic acid ion pair of bisoprolol to complex
Complex, for maleic acid bisoprolol ion-pair complexes, bisoprolol fumarate's ion-pair complexes, tartaric acid bisoprolol
One or more in ion-pair complexes, benzenesulfonic acid bisoprolol ion-pair complexes, and synthesis by the following method:
(1) bisoprolol free alkali is dissolved in acetone
(2) add and bisoprolol free alkali equimolar or the organic acid of half molal quantity
(3) room temperature uniform stirring is after 2 hours, and solvent evaporated obtains target product
Transdermal absorption accelerator includes alcohols, fitter acids and its ester class, surfactant-based, terpenes, amine, amide
Class, amino acids and ester thereof or phospholipids compounds, such as sorbester p17, azone, oleic acid, menthol, N-Methyl pyrrolidone, meat
Isopropyl myristate, will select one or more in above-mentioned accelerator, wherein preferred sorbester p17, azone, N-crassitude
Two or three combination in ketone, the more preferably combination of these three accelerator, when for both or during the combination of three, its ratio is divided
Wei 0.5:1～2:1 or 0.5:0.5:1～2:2:1.Transdermal absorption accelerator account for medicine carrying pressure-sensitive adhesive layer gross weight 0wt%～
15wt%, preferably 5wt%～15wt%.Host material selected by pressure sensitive adhesive is silicone, polyisobutylene class, polyacrylate
One or more in class or cellulose family and their derivant, the wherein pressure-sensitive acrylate of preferred hydroxyl, its
Consumption is 80wt%～94.5wt%.
The patch preparation technology of the present invention is: the organic acid ion of indapamide with bisoprolol be dissolved in complex
In organic solvent, and it is scattered in the pressure sensitive adhesive of certain mass.It is sufficiently stirred for rear transfer coated in adherent layer, does through 20～60 DEG C
Dry 10～20 minutes, backing layer cover, be die-cut into a certain size, specification, i.e. make indapamide bisoprolol percutaneous absorbtion patch
Agent.Medicine carrying pressure-sensitive adhesive layer thickness can be 30～100 μm.
Ion pair strategy and chemical promoter are organically combined by the present invention, complete in transdermal skin patches indapamide and
Bisoprolol percutaneous is through the two-ways regulation of ability, it is achieved that two medicines pass through from the synchronized of transdermal skin patches.
Detailed description of the invention:
The present invention is explained in more detail by following example, it should be apparent that: the present invention is never limited to embodiment, or only
Show as embodiment.
Embodiment 1
2g bisoprolol fumarate being dissolved in 5ml distilled water, dropping 20% (w/v) aqueous sodium carbonate is to no longer having
Oily liquids produces.Divide 3 extractions, combining extraction liquid by 240ml ethyl acetate, add appropriate anhydrous sodium sulfate and take off
Water, then rotary evaporation is drying to obtain bisoprolol free alkali.
Embodiment 2
0.1mol bisoprolol free alkali is dissolved in 40ml acetone, under agitation adds 0.05mol maleic acid, continue
Stirring 2 hours, rotary evaporation volatilizes solvent and i.e. obtains maleic acid bisoprolol ion-pair complexes.
Embodiment 3
0.1mol bisoprolol free alkali is dissolved in 40ml acetone, under agitation adds 0.05mol fumaric acid, continue
Stirring 2 hours, rotary evaporation volatilizes solvent and i.e. obtains bisoprolol fumarate's ion-pair complexes.
Embodiment 4
0.1mol bisoprolol free alkali is dissolved in 40ml acetone, under agitation adds 0.1mol tartaric acid, continue
Stirring 2 hours, rotary evaporation volatilizes solvent and i.e. obtains tartaric acid bisoprolol ion-pair complexes.
Embodiment 5
0.1mol bisoprolol free alkali is dissolved in 40ml acetone, under agitation adds 0.1mol benzenesulfonic acid, continue
Stirring 2 hours, rotary evaporation volatilizes solvent and i.e. obtains benzenesulfonic acid bisoprolol ion-pair complexes.
Embodiment 6
By 0.05mmol indapamide and 0.05mmol bisoprolol free alkali and 1.2g pressure-sensitive acrylate DT-
2287 fully mix, and are dried 15 minutes through 50 DEG C, then cover with the back lining materials including PVC or non-woven fabrics, die-cut, make
Thickness is the patch of 30 μm.
Embodiment 7
By 0.05mmol indapamide and 0.05mmol bisoprolol maleic acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-2287 fully mixes, and is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics
Lid, die-cut, make the patch that thickness is 30 μm.
Embodiment 8
By 0.05mmol indapamide and 0.05mmol bisoprolol fumaric acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-2287 fully mixes, and is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics
Lid, die-cut, make the patch that thickness is 30 μm.
Embodiment 9
By 0.05mmol indapamide and 0.05mmol bisoprolol tartaric acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-2287 fully mixes, and is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics
Lid, die-cut, make the patch that thickness is 30 μm.
Embodiment 10
By 0.05mmol indapamide and 0.05mmol bisoprolol benzenesulfonic acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-2287 fully mixes, and is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics
Lid, die-cut, make the patch that thickness is 30 μm.
Embodiment 11
By 0.05mmol indapamide and 0.05mmol bisoprolol tartaric acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-2510 fully mixes, and is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics
Lid, die-cut, make the patch that thickness is 30 μm.
Embodiment 12
By 0.05mmol indapamide and 0.05mmol bisoprolol tartaric acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-4098 fully mixes, and is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics
Lid, die-cut, make the patch that thickness is 30 μm.
Embodiment 13
By 0.05mmol indapamide and 0.05mmol bisoprolol tartaric acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-9301 fully mixes, and is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics
Lid, die-cut, make the patch that thickness is 30 μm.
Embodiment 14
By 0.05mmol indapamide and 0.05mmol bisoprolol tartaric acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-2677, is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics, die-cut,
Make the patch that thickness is 30 μm.
Embodiment 15
By 0.05mmol indapamide and 0.05mmol bisoprolol tartaric acid ion-pair complexes and 1.2g acrylate
Class pressure sensitive adhesive DT-2852 fully mixes, and is dried 15 minutes through 50 DEG C, then covers with the back lining materials including PVC or non-woven fabrics
Lid, die-cut, make the patch that thickness is 30 μm.
Embodiment 16
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g sorbester p17, with
1.2g pressure-sensitive acrylate DT-2287 fully mixes, and is dried 15 minutes through 50 DEG C, then with including PVC or non-woven fabrics
Back lining materials cover, die-cut, make the patch that thickness is 30 μm.
Embodiment 17
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g oleic acid, with
1.2g pressure-sensitive acrylate DT-2287 fully mixes, and is dried 15 minutes through 50 DEG C, then with including PVC or non-woven fabrics
Back lining materials cover, die-cut, make the patch that thickness is 30 μm.
Embodiment 18
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion pair, 0.06g isopropyl myristate,
Fully mix with 1.2g pressure-sensitive acrylate DT-2287, be dried 15 minutes through 50 DEG C, then with including PVC or nonwoven
The back lining materials of cloth covers, die-cut, makes the patch that thickness is 30 μm.
Embodiment 19
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g azone, with
1.2g pressure-sensitive acrylate DT-2287 fully mixes, and is dried 15 minutes through 50 DEG C, then with including PVC or non-woven fabrics
Back lining materials cover, die-cut, make the patch that thickness is 30 μm.
Embodiment 20
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g menthol, with
1.2g pressure-sensitive acrylate DT-2287 fully mixes, and is dried 15 minutes through 50 DEG C, then with including PVC or non-woven fabrics
Back lining materials cover, die-cut, make the patch that thickness is 30 μm.
Embodiment 21
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06gN-methylpyrrole
Alkanone, fully mixes with 1.2g pressure-sensitive acrylate DT-2287, through 50 DEG C be dried 15 minutes, then with include PVC or
The back lining materials of non-woven fabrics covers, die-cut, makes the patch that thickness is 30 μm.
Embodiment 22
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g azone, 0.06g
Menthol, fully mixes with 1.2g pressure-sensitive acrylate DT-2287, is dried 15 minutes through 50 DEG C, then with including PVC
Or the back lining materials of non-woven fabrics covers, die-cut, make the patch that thickness is 30 μm.
Embodiment 23
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g menthol,
0.06g sorbester p17, fully mixes with 1.2g pressure-sensitive acrylate DT-2287, is dried 15 minutes through 50 DEG C, then with bag
The back lining materials including PVC or non-woven fabrics covers, die-cut, makes the patch that thickness is 30 μm.
Embodiment 24
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g sorbester p17,
0.06g azone, fully mixes with 1.2g pressure-sensitive acrylate DT-2287, is dried 15 minutes through 50 DEG C, then with including
The back lining materials of PVC or non-woven fabrics covers, die-cut, makes the patch that thickness is 30 μm.
Embodiment 25
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g menthol,
0.06g N-Methyl pyrrolidone, fully mixes with 1.2g pressure-sensitive acrylate DT-2287, is dried 15 points through 50 DEG C
Clock, then covers with the back lining materials including PVC or non-woven fabrics, die-cut, makes the patch that thickness is 30 μm.
Embodiment 26
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g azone, 0.06g
N-Methyl pyrrolidone, fully mixes with 1.2g pressure-sensitive acrylate DT-2287, through 50 DEG C be dried 15 minutes, then
Cover with the back lining materials including PVC or non-woven fabrics, die-cut, make the patch that thickness is 30 μm.
Embodiment 27
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g sorbester p17,
0.06g N-Methyl pyrrolidone, fully mixes with 1.2g pressure-sensitive acrylate DT-2287, is dried 15 points through 50 DEG C
Clock, then covers with the back lining materials including PVC or non-woven fabrics, die-cut, makes the patch that thickness is 30 μm.
Embodiment 28
By 0.05mmol indapamide, 0.05mmol bisoprolol tartaric acid ion-pair complexes, 0.06g azone, 0.06g
Sorbester p17,0.06g N-Methyl pyrrolidone, fully mix with 1.2g pressure-sensitive acrylate DT-2287, does through 50 DEG C
Dry 15 minutes, then cover with the back lining materials including PVC or non-woven fabrics, die-cut, make the patch that thickness is 30 μm.
The present invention selects indopamide, bisoprolol free alkali or its organic acid ion molar ratio to complex simultaneously
Testing for 0.5:1 and 2:1, its result is close with 1:1 result, show indopamide, bisoprolol free alkali or its have
In the range of the molar ratio of machine ion pair complex is 0.5:1～2:1, Drug Percutaneous Absorption effect is had no significant effect.
Test example 1
In-vitro percutaneous test:
The male rabbit of about 1.5Kg is anaesthetized with 20% urethane, cuts off belly wool, more carefully will with electric shaver
Remaining hair is rejected clean, and auricular vein is injected air and put to death rabbit, peels off skin, removes subcutaneous fat, rushes with normal saline
It is in store in-70 DEG C after wash clean.
Employing horizontal dual chamber diffusion cell carries out drug percutaneous permeability test, and effective diffusion area is 0.95cm2, reception tank fills
There is the phosphate buffered solution of 3.0ml pH7.4.Patch is pasted and keratodermatitis, is fixed on reception tank, spot sampling
2ml, supplements 2ml blank and receives liquid.Continuing magnetic force stirring in process of the test, mixing speed is 600～800rpm, uses periphery to follow
The temperature of ring water-bath maintenance system is 32 DEG C.
The impact on bisoprolol indapamide percutaneous absorption patch Chinese medicine percutaneous transit dose of the table 1 ion pair strategy
(Mean ± S.D.) (n=4)
| Embodiment | Q24hBSP(μg/cm2) | Q24hIND(μg/cm2) | RBSP/IND |
| 6 | 158.19±10.34 | 9.84±2.09 | 16.08 |
| 7 | 60.57±6.77 | 9.05±2.45 | 6.70 |
| 8 | 17.43±2.76 | 10.65±3.58 | 1.50 |
| 9 | 11.03±3.96 | 8.73±1.64 | 1.26 |
| 10 | 5.23±1.89 | 9.15±1.55 | 0.57 |
Q24hThe percutaneous transit dose of bisoprolol in patch in BSP:24 hour, represents the percutaneous of bisoprolol through ability.
Q24hThe percutaneous transit dose of bisoprolol in patch in IND:24 hour, represents the percutaneous of bisoprolol through ability.
RBSP/IND: Q24hBSP and Q24hThe ratio of IND
Conclusion: after the ion-pair complexes that bisoprolol and organic acid are formed, it is possible to the percutaneous of regulation and control bisoprolol passes through
Ability, and when selecting tartaric acid ion-pair complexes, the percutaneous of bisoprolol is reduced to indapamide ability substantially through ability
Equal.
The impact that indapamide bisoprolol transdermal skin patches Chinese medicine is passed through by table 2 variety classes acrylate pressure sensitive adhesive
(Mean ± S.D.) (n=4)
Conclusion: the Percutaneous permeability of the pressure sensitive adhesive of hydroxy functional groups is the highest, is secondly the pressure sensitive adhesive without functional group, containing carboxylic
The pressure sensitive adhesive Percutaneous permeability of base functional group is minimum.
Bisoprolol indapamide percutaneous absorption patch Chinese medicine percutaneous is passed through by table 3 chemical promoter and associating accelerator
The impact (Mean ± S.D.) (n=4) of amount
| Embodiment | Q24hBSP(μg/cm2) | ER(BSP) | Q24hIND(μg/cm2) | ER(IND) |
| 16 | 24.20±5.21 | 2.19 | 14.48±4.02 | 1.66 |
| 17 | 12.73±2.69 | 1.15 | 6.59±2.07 | 0.76 |
| 18 | 12.48±2.52 | 1.13 | 9.10±2.07 | 1.04 |
| 19 | 16.11±4.02 | 1.46 | 14.75±3.27 | 1.69 |
| 20 | 17.04±4.28 | 1.54 | 15.13±4.11 | 1.73 |
| 21 | 11.92±2.27 | 1.08 | 11.23±1.33 | 1.29 |
| 22 | 19.76±3.19 | 1.79 | 9.11±3.44 | 1.04 |
| 23 | 25.46±9.57 | 2.31 | 12.08±9.01 | 1.38 |
| 24 | 40.62±7.74 | 3.68 | 22.63±9.31 | 2.59 |
| 25 | 10.18±2.18 | 0.92 | 11.25±4.66 | 1.29 |
| 26 | 23.05±4.37 | 2.09 | 34.02±4.33 | 3.90 |
| 27 | 28.47±2.68 | 2.58 | 31.31±3.83 | 3.59 |
| 28 | 36.80±7.70 | 3.34 | 33.15±7.52 | 3.80 |
ER (BSP): Q24hBSP (accelerator) and Q24hThe ratio of BSP (blank), i.e. compared with being not added with chemical promoter, changes
Learn accelerator to the promotion tranmittance of bisoprolol in patch.
ER (IND): Q24hIND (accelerator) and Q24hThe ratio of IND (blank), i.e. compared with being not added with chemical promoter, changes
Learn accelerator to the promotion tranmittance of indapamide in patch.
Conclusion: the transit dose of bisoprolol ion-pair complexes and indapamide in patch can be carried out by chemical promoter
Promote, and the facilitation effect of some associating accelerator is better than single accelerator.Sorbester p17 is combined for a peso Lip river with azone
Your facilitation is optimum.Azone is combined with N-Methyl pyrrolidone, and sorbester p17 is combined Yin with N-Methyl pyrrolidone
The facilitation reaching handkerchief amine is optimum.Sorbester p17, azone, three kinds of accelerator of N-Methyl pyrrolidone combine the promotion to two medicines
Effect is the most optimum, and each of which component accelerator dosage is 0.06g.
Claims (28)
1. indapamide bisoprolol transdermal skin patches, is made up of backing layer, medicine carrying pressure-sensitive adhesive layer and adherent layer, it is characterised in that
Medicine carrying pressure-sensitive adhesive layer include indapamide, bisoprolol organic acid ion to complex, pressure sensitive adhesive, transdermal absorption accelerator, its
Middle indapamide, bisoprolol organic acid ion dose total to complex account for medicine carrying pressure-sensitive adhesive layer gross weight 0.5 wt %～
5.5 wt %, wherein indopamide, bisoprolol organic acid ion are 0.5: 1～2: 1 to the molar ratio of complex, institute
State transdermal absorption accelerator and account for the 0 wt %～15 wt % of gross weight.
Indapamide bisoprolol transdermal skin patches the most according to claim 1, it is characterised in that: described bisoprolol has
Machine ion pair complex is the pharmaceutically acceptable organic acid ion of bisoprolol to complex, for maleic acid bisoprolol from
Son is to complex, bisoprolol fumarate's ion-pair complexes, tartaric acid bisoprolol ion-pair complexes, benzenesulfonic acid peso Lip river
One or more in your ion-pair complexes.
Indapamide bisoprolol transdermal skin patches the most according to claim 1 and 2, it is characterised in that: described peso Lip river
Your organic acid ion is bisoprolol tartaric acid ion-pair complexes to complex.
Indapamide bisoprolol transdermal skin patches the most according to claim 1 and 2, it is characterised in that: described peso Lip river
Complex is synthesized by organic acid ion by by the following method:
Bisoprolol free alkali is dissolved in acetone；
Add and bisoprolol free alkali equimolar or the organic acid of half molal quantity；
After room temperature uniform stirring 2 hours, solvent evaporated, obtain target product.
Indapamide bisoprolol transdermal skin patches the most according to claim 3, it is characterised in that: described bisoprolol has
Machine ion pair complex synthesizes by the following method:
Bisoprolol free alkali is dissolved in acetone；
Add and bisoprolol free alkali equimolar or the organic acid of half molal quantity；
After room temperature uniform stirring 2 hours, solvent evaporated, obtain target product.
6. according to the indapamide bisoprolol transdermal skin patches described in claim 1,2 or 5, it is characterised in that: selected by pressure sensitive adhesive
Host material be the one in silicone, polyisobutylene class, polyacrylate or cellulose family and their derivant
Or multiple, its consumption is 80 w t %～94.5 wt %.
Indapamide bisoprolol transdermal skin patches the most according to claim 3, it is characterised in that: the base selected by pressure sensitive adhesive
Material is one or more in silicone, polyisobutylene class, polyacrylate or cellulose family and their derivant,
Its consumption is 80 w t %～94.5 wt %.
Indapamide bisoprolol transdermal skin patches the most according to claim 4, it is characterised in that: the base selected by pressure sensitive adhesive
Material is one or more in silicone, polyisobutylene class, polyacrylate or cellulose family and their derivant,
Its consumption is 80 w t %～94.5 wt %.
9. according to the indapamide bisoprolol transdermal skin patches described in claim 1,2 or 5, it is characterised in that: pressure sensitive adhesive is for containing
The pressure-sensitive acrylate of hydroxyl.
Indapamide bisoprolol transdermal skin patches the most according to claim 3, it is characterised in that: pressure sensitive adhesive is hydroxyl
Pressure-sensitive acrylate.
11. indapamide bisoprolol transdermal skin patches according to claim 4, it is characterised in that: pressure sensitive adhesive is hydroxyl
Pressure-sensitive acrylate.
12. according to the indapamide bisoprolol transdermal skin patches described in claim 1,2,5,7,8,10 or 11, it is characterised in that:
Transdermal absorption accelerator includes alcohols, fitter acids and its ester class, surfactant-based, terpenes, amine, amide-type, aminoacid
Class and ester thereof or phospholipids compounds, its consumption is 5 wt～15 wt % of medicine carrying pressure-sensitive adhesive layer weight.
13. indapamide bisoprolol transdermal skin patches according to claim 3, it is characterised in that: transdermal absorption accelerator
Including alcohols, fitter acids and its ester class, surfactant-based, terpenes, amine, amide-type, amino acids and ester thereof or phospholipid
Compounds, its consumption is 5 wt～15 wt % of medicine carrying pressure-sensitive adhesive layer weight.
14. indapamide bisoprolol transdermal skin patches according to claim 4, it is characterised in that: transdermal absorption accelerator
Including alcohols, fitter acids and its ester class, surfactant-based, terpenes, amine, amide-type, amino acids and ester thereof or phospholipid
Compounds, its consumption is 5 wt～15 wt % of medicine carrying pressure-sensitive adhesive layer weight.
15. indapamide bisoprolol transdermal skin patches according to claim 6, it is characterised in that: transdermal absorption accelerator
Including alcohols, fitter acids and its ester class, surfactant-based, terpenes, amine, amide-type, amino acids and ester thereof or phospholipid
Compounds, its consumption is 5 wt～15 wt % of medicine carrying pressure-sensitive adhesive layer weight.
16. indapamide bisoprolol transdermal skin patches according to claim 9, it is characterised in that: transdermal absorption accelerator
Including alcohols, fitter acids and its ester class, surfactant-based, terpenes, amine, amide-type, amino acids and ester thereof or phospholipid
Compounds, its consumption is 5 wt～15 wt % of medicine carrying pressure-sensitive adhesive layer weight.
17. paste according to the indapamide bisoprolol percutaneous described in claim 1,2,5,7,8,10,11,13,14,15 or 16
Agent, it is characterised in that: described transdermal absorption accelerator is sorbester p17, azone, oleic acid, menthol, N-Methyl pyrrolidone, meat
One or more in isopropyl myristate.
18. indapamide bisoprolol transdermal skin patches according to claim 3, it is characterised in that: described percutaneous absorbtion
Accelerator is one or more in sorbester p17, azone, oleic acid, menthol, N-Methyl pyrrolidone, isopropyl myristate.
19. indapamide bisoprolol transdermal skin patches according to claim 4, it is characterised in that: described percutaneous absorbtion
Accelerator is one or more in sorbester p17, azone, oleic acid, menthol, N-Methyl pyrrolidone, isopropyl myristate.
20. indapamide bisoprolol transdermal skin patches according to claim 6, it is characterised in that: described percutaneous absorbtion
Accelerator is one or more in sorbester p17, azone, oleic acid, menthol, N-Methyl pyrrolidone, isopropyl myristate.
21. indapamide bisoprolol transdermal skin patches according to claim 9, it is characterised in that: described percutaneous absorbtion
Accelerator is one or more in sorbester p17, azone, oleic acid, menthol, N-Methyl pyrrolidone, isopropyl myristate.
22. indapamide bisoprolol transdermal skin patches according to claim 12, it is characterised in that: described percutaneous absorbtion
Accelerator is one or more in sorbester p17, azone, oleic acid, menthol, N-Methyl pyrrolidone, isopropyl myristate.
23. indapamide bisoprolol transdermal skin patches according to claim 17, it is characterised in that: described percutaneous absorbtion
Accelerator is that two or three in sorbester p17, azone, N-Methyl pyrrolidone is used in combination.
24. according to the indapamide bisoprolol transdermal skin patches described in claim 18-22 any one, it is characterised in that: institute
The transdermal absorption accelerator stated is that two or three in sorbester p17, azone, N-Methyl pyrrolidone is used in combination.
25. indapamide bisoprolol transdermal skin patches according to claim 17, it is characterised in that: described percutaneous absorbtion
Accelerator is the combination of sorbester p17, azone, N-Methyl pyrrolidone.
26. according to the indapamide bisoprolol transdermal skin patches described in claim 18-23 any one, it is characterised in that: institute
The transdermal absorption accelerator stated is the combination of sorbester p17, azone, N-Methyl pyrrolidone.
27. indapamide bisoprolol transdermal skin patches according to claim 17, it is characterised in that: transdermic absorbent is taken charge of
The ratio of two or three in dish 80, azone, N-Methyl pyrrolidone is 0.5:1～2:1 or 0.5:0.5:1～2:2:1.
28. according to the indapamide bisoprolol transdermal skin patches described in claim 18-23 any one, it is characterised in that: warp
In skin absorbent in sorbester p17, azone, N-Methyl pyrrolidone two or three ratio be 0.5:1～2:1 or 0.5:
0.5:1～2:2:1.
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