CN107320463A - A kind of slow-release transdermal patch containing Isosorbide Mononitrate and its application - Google Patents
A kind of slow-release transdermal patch containing Isosorbide Mononitrate and its application Download PDFInfo
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- CN107320463A CN107320463A CN201710556567.0A CN201710556567A CN107320463A CN 107320463 A CN107320463 A CN 107320463A CN 201710556567 A CN201710556567 A CN 201710556567A CN 107320463 A CN107320463 A CN 107320463A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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Abstract
The present invention relates to a kind of slow-release transdermal patch containing Isosorbide Mononitrate and its application; the slow-release transdermal patch is made up of back sheet, pastille storage layer, anti-sticking protective layer; described pastille storage layer; its preparation method is; Isosorbide Mononitrate is uniformly mixed with macromolecule sticky stuff or pressure sensitive adhesive, is applied on back sheet, heating, drying; pastille storage layer is made, wherein macromolecule sticky stuff or pressure sensitive adhesive is selected from：Water-soluble acrylic pressure sensitive adhesive, fat-soluble acrylate pressure sensitive adhesive, organic silicon pressure sensitive adhesive, Medical PSA, contain transdermal enhancer in the pastille storage layer, it, which is selected from azone, oleic acid, glyceryl triacetate, isopropyl myristate, the pastille storage layer, contains crystallization inhibitor octadecyl alcolol.
Description
Technical field
The invention belongs to technical field of medicine, in particular to a kind of medicine external application slow-release transdermal preparation, especially
It is related to a kind of slow-release transdermal preparation containing Isosorbide Mononitrate and its application.
Background technology
Isosorbide Mononitrate is the major active metabolite product of ISDN.As other organic nitrates,
Isosorbide Mononitrate discharges nitric oxide, and nitric oxide increases cGMP by activating guanylate cyclase, activates cGMP
Deopendent protein kinase, changes the ring phosphorization of various albumen in smooth muscle cell, so that relaxation vascular smooth muscle.Single nitric acid
Soquad is distended the blood vessels by relaxation vascular smooth muscle, expansible peripheral arterial and vein.Vein is made by expansion of veins
Capacity increase, reduces returned blood volume, so as to reduce ventricular end diastolic pressure and volume (preload).Pass through expansion artery and petty action
Arteries and veins reduction systemic vascular resistance (afterload), myocardium work done is reduced；The reduction of load before and after heart, so as to reduce myocardial oxygen consumption
Amount.Moreover, when because of artery sclerosis partial blockage coronary artery, the big coronary artery of Isosorbide Mononitrate alternative expansion,
The redistribution of myocardial blood flow can be promoted, make the increase of coronary perfusion amount, nitrate esters can also expand coronary stenosis position, Yi Jihuan
Solve coronary spasm.Isosorbide Mononitrate passes through above-mentioned effect function of resisting myocardial ischemia.The acute toxicity of rat and mouse is ground
Study carefully and show, oral LD50 is about 2000-2500mg/kg, carried out the long term toxicity research of 78 weeks and 52 weeks respectively to mouse and dog,
Toxic reaction is respectively occurring at dosage 405mg/kg and 90mg/kg first.Fecundity research is carried out to two generation mouse, to mouse
Teratogenesis Journal of Sex Research has been carried out with rabbit, under parent intoxicating dosage, has not found that Isosorbide Mononitrate has teratogenesis.To single nitric acid
External, the internal mutagenesis Journal of Sex Research of Soquad shows that all Mutagenicity tests are feminine gender.The either length of mouse and rabbit
Phase toxicity test, or carcinogenesis, table are not found to mouse 125 weeks (male), and the carcinogenic Journal of Sex Research of 138 weeks (female)
Bright Isosorbide Mononitrate is to the mankind without carcinogenesis.
Isosorbide Mononitrate is adapted to the long-term treatment of coronary heart disease；Anginal prevention；Continue the heart after myocardial infarction to twist
The treatment of pain；With digitalis and/or diuretics use in conjunction, chronic congestive heart failure is treated；The long-term treatment of coronary heart disease
With prevention angina pectoris attacks, the treatment after myocardial infarction is also applied for.
The existing Isosorbide Mononitrate preparation listed both at home and abroad is oral tablet, ejection preparation.According to the literature, it is single
ISDN oral absorption is rapid, and 1 hour blood concentration peaking after medication, single takes the Cmax of this product 20mg tablets
For 360 μ g/L, absorption of the food on this product does not influence, and no liver first-pass effect, bioavilability partly declines up to 90-100%
Phase is 4~5 hours, and plasma protein binding rate is low (＜ 4%).Isosorbide Mononitrate is almost metabolized completely in liver, denitration
Almost all is arranged in the form of metabolite isobide (being about 37%) and dextrorotation sorbierite (about 7%) through kidney by urine afterwards
Go out in vitro, 25% discharge, only about 2% medicine is discharged with original shape, arranged in excrement in glucuronide conjugate form in addition
Go out ＜ 1%, its metabolite is all without vasodilative effect.Hepatopath occurs without cumulative appearance.Evidence suggests health volunteer
It is similar with the blood characteristics for suffering from chronic stable angina patient.Isosorbide Mononitrate can be removed through dialysis.
General oral medication, has blood concentration shakiness, the individual difference of medication, same dosage and effect is different, and
Isosorbide Mononitrate half-life short, one takes medicine 2~3 times day by day, causes the compliance (biddability) of oral formulations poor, especially right
In particular patients ' it is difficult to accomplish to take medicine on time, the treatment use of Isosorbide Mononitrate is more limited.Thus highly desirable exploitation
The alternative drugs of novel form.Chinese patent discloses following patch：
| 00130223.X | Isosorbide dinitrate plaster for first aid | 2000-10-31 |
| 201010200120.8 | Isosorbide dinitrate patch and preparation method thereof | 2010-06-13 |
| 98800181.0 | Patch containing ISDN | 1998-01-06 |
| 200580052536.7 | Transdermal patch containing ISDN and bisoprolol | 2005-12-09 |
Patch disclosed in prior art is mainly used in first aid, and rate of release is fast, but drug release perseverance degree is poor, it is impossible to rise for a long time
Effect, obtained patch stability is poor, often crystallizes, the problems such as degraded.The sustained release containing Isosorbide Mononitrate of the present invention
Transdermal patch drug release is equal permanent, action temperature and and it is lasting, dosage rate is significantly reduced compared with oral tablet, and patient compliance is more
It is good, make angina pectoris long-term treatment and prevention be easier to become a reality, and the present invention external application slow-release transdermal preparation due to being administered and removing
Just, be particularly suitable for use in prescription the patient that cannot be administered orally, and being such as applied to may during prevention corrective surgery in openheart surgery
The angina pectoris of generation, has filled up the blank of such clinical application.
The content of the invention
The present invention to change the original oral administration route of Isosorbide Mononitrate, invent it is a kind of it is brand-new, with single nitric acid
Soquad sustained release transdermal patches novel form is pharmaceutical carrier, the new method of administration and method by percutaneous drug delivery.
It is an object of the present invention to because having half when overcoming Isosorbide Mononitrate oral medication angina pectoris in the prior art
Declining, the phase is short, and administration is frequent, it is difficult to realize the optimal steady treatment and prevention effect of patient with angina pectoris, it is impossible to make in a long time
Medicine is to approach the problem of constant speed is into shortcoming in human body.There is provided a kind of stability splendid, it is long-acting, inhaled by skin
The receive, therapeutic effect that action is gentle, blood concentration is balanced, stable, good patient compliance is carried with easy to use containing single nitre
The slow-release transdermal patch of sour Soquad medicine.
It is a further object of the invention to provide a kind of preparation method of the slow-release transdermal patch.
The purpose of the present invention is achieved through the following technical solutions：
Slow-release transdermal patch of the invention containing Isosorbide Mononitrate, active ingredient is Isosorbide Mononitrate, this hair
It is bright to be not limited to any Isosorbide Mononitrate and/or the concrete form of its salt.
The present invention provides a kind of Isosorbide Mononitrate slow-release transdermal patch, it is characterised in that the slow-release transdermal patch
It is made up of back sheet, pastille storage layer, anti-sticking protective layer, described pastille storage layer, its preparation method is, by the different mountain of single nitric acid
Pear ester is uniformly mixed with macromolecule sticky stuff or pressure sensitive adhesive, is applied on back sheet, heating, drying, and pastille storage layer is made, its
Middle macromolecule sticky stuff or pressure sensitive adhesive are selected from：Water-soluble acrylic pressure sensitive adhesive, fat-soluble acrylate pressure sensitive adhesive, organic silicon pressure
Quick glue, Medical PSA, the amount of pbz polymer sticky stuff or pressure sensitive adhesive every square centimeter is 1.0-30.0mg, accounts for sustained release
The 70.0~95.0% of transdermal patch weight；Contain transdermal enhancer in the pastille storage layer, it is selected from azone, oleic acid, three
Acetin, isopropyl myristate, wherein the amount every square centimeter containing transdermal enhancer is 0-1.0mg, account for slow-release transdermal
The 0-10.0% of patch weight；Contain crystallization inhibitor octadecyl alcolol in the pastille storage layer, wherein every square centimeter containing crystallization
The amount of inhibitor is 0.05~0.4mg, accounts for the 0.3-5.0% of slow-release transdermal patch weight；The different mountain every square centimeter containing single nitric acid
The amount of pear ester is 0.3~3.0mg.
It is surprisingly found by the inventors that, Isosorbide Mononitrate slow-release transdermal patch prepared by the present invention is through remarkable isolated skin
Permeation test in vitro determine, its percutaneous rate maximum can reach daily 9.12mg/10cm2, according to Isosorbide Mononitrate
20.0~60.0mg of oral formulations consumption per day is calculated, it is only necessary to which daily 1 patch 22cm2~66cm2 paster is that can reach lasting maximum
The purpose of day dosage treatment, different dosages can be easily achieved by adjusting paster area.
Slow-release transdermal patch of the invention containing Isosorbide Mononitrate, the amount every square centimeter containing Isosorbide Mononitrate
For 0.3~3.0mg, wherein it is preferred that 0.3~2.5mg, more preferably 0.5~2.0mg；
Slow-release transdermal patch of the invention containing Isosorbide Mononitrate, the transdermal amount applied to human body skin is daily
10.0~60.0mg, preferably 20.0~60.0mg.
Currently preferred slow-release transdermal patch, wherein, the pressure sensitive adhesive is selected from：Fat-soluble acrylate pressure sensitive adhesive, it is described
Transdermal enhancer is selected from：Azone, crystallization inhibitor is selected from：Octadecyl alcolol, solvent is selected from：Ethyl acetate；Wherein, the weight of each component
Proportioning is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add fat-soluble Acrylate pressure sensitive
Glue is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then up-protective layer is covered, 3.
Size is cut on demand, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made.
Slow-release transdermal patch specifically preferred according to the invention, is formulated as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add fat-soluble Acrylate pressure sensitive
Glue is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then covers up-protective layer, 3.
Size is cut on demand, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made；
Or
Formula is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add fat-soluble Acrylate pressure sensitive
Glue is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then up-protective layer is covered, 3.
Size is cut on demand, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made.
The pleasantly surprised discovery of inventor, the slow-release transdermal patch of the invention containing Isosorbide Mononitrate adds octadecyl alcolol
As crystallization inhibitor, slow-release transdermal patch system is set to exempt crystalline polamer.And on the contrary, comparative example (does not add crystallization suppression
System), there is substantial amounts of crystallization after three months, crystallize the percutaneous rate by Isosorbide Mononitrate is directly affected.
The slow-release transdermal patch containing Isosorbide Mononitrate of the present invention, in addition to appropriate medically acceptable tax
Shape agent and transdermal enhancer.
The slow-release transdermal patch containing Isosorbide Mononitrate of the present invention, its preparation method is：By the different sorb of single nitric acid
Ester, transdermal enhancer are mixed with the auxiliary material such as suitable macromolecule sticky stuff or pressure sensitive adhesive, transdermal enhancer, are applied to back lining materials
On, heating, drying, then up-protective layer is covered, size is cut on demand, packaging, that is, the sustained release containing Isosorbide Mononitrate is made saturating
Skin patch.
The Isosorbide Mononitrate slow-release transdermal patch of the present invention, wherein the macromolecule sticky stuff or pressure sensitive adhesive, can
Think water-soluble acrylic pressure sensitive adhesive, fat-soluble acrylate pressure sensitive adhesive, or organic silicon pressure sensitive adhesive, polyacrylate pressure
Quick glue.
The Isosorbide Mononitrate slow-release transdermal patch of the present invention, in addition to appropriate medically acceptable excipient,
Including plasticizer such as acetic acid triethyl, triethyl citrate, atoleine and various glyceride can be contained；Suppression can be contained
Microbial inoculum such as parabens, sorbic acid, benzoic acid；Solubilizer such as propane diols, Tweens, polyethylene glycols can be contained.
The invention provides the new medication that a kind of Isosorbide Mononitrate passes through percutaneous drug delivery.
Coronary heart disease is used for by the new medication of percutaneous drug delivery present invention also offers a kind of Isosorbide Mononitrate
Long-term treatment, anginal prevention, the purposes for continuing anginal treatment after myocardial infarction.
External use plaster of the present invention, its back sheet can be aluminium foil, PE films, PET film, EVA film or non-woven fabrics, protection
Layer is the PET film after release treatment.This patch can do rectangularity, square, circle, ellipse, triangle or two kinds with
The combination of upper figure it is variously-shaped；The preparation technology of patch is spreading formation process or extrusion forming process；Patch is affixed on body
Body skin surface is used.
The positive effect of the present invention
The slow-release transdermal patch containing Isosorbide Mononitrate of the present invention has it unique compared with Convenient oral administration method
Advantage：(1) single administration can make medicine in a long time to approach constant speed into human body, similar to for a long time
Drip-feed；(2) interference and the degradation of gastrointestinal factors are avoided, toxic side effect of the medicine to human body had both been reduced,
The individual difference of medication is reduced again；(3) it can maintain close to constant effective blood concentration, it is to avoid other medications are produced
Blood concentration Wave crest and wave trough phenomenon, realize steady therapeutic effect；(4) it is easy to use, easily it is accepted by patients, i.e. patient
Compliance is good.(5) administration can be terminated at any time, improve drug safety.(6) addition octadecyl alcolol makes to delay as crystallization inhibitor
Release transdermal patch system and exempt crystalline polamer.And on the contrary, comparative example (not adding crystallization to suppress), has substantial amounts of knot after three months
Crystalline substance, octadecyl alcolol prevents that the effect that crystallization is produced is particularly evident, can better ensure that Isosorbide Mononitrate sustained release transdermal patch
The stability of percutaneous rate of the agent in long-term placement process.
The slow-release transdermal patch containing Isosorbide Mononitrate of the present invention, release process is close to zero level within its external 24 hours
Rate process, dermal penetration rate is close to constant speed.Stability is good, favorable reproducibility, and stickup property is good, especially with azone, ten
Eight alcohol, ethyl acetate, fat-soluble acrylate pressure-sensitive adhesive is formulated it as patch of the present invention and shows excellent in various detections,
Particularly content and impurity is changed very little, and long-term to place color and stickup property is changed very little, performance is better than other formulas.
Brief description of the drawings：
The slow-release transdermal patch containing ISDN of Fig. 1 present invention is in cavy and people from daily transdermal on skin
Amount contrast
The slow-release transdermal patch In-vitro release curves containing Isosorbide Mononitrate of Fig. 2 present invention
Found out by Fig. 1, Fig. 2, the coefficient correlation of its linear regression illustrates this product in guinea pig skin body more than 0.99
Outer transdermal process and human body skin meet zero order process in transdermal process, the release in vitro process of body, and slow release effect is good
It is good.The purpose of design of preparation controlled release is reached.
Embodiment
The present invention is further illustrated with embodiment, it should be understood that these embodiments are only used for explanation originally below
Invention, rather than for limiting the present invention.Because the specific preparation method of following examples has no particular/special requirement, therefore do not do individually
Explanation.
In embodiment, Isosorbide Mononitrate used, the raw material as excipient, transdermal enhancer, are commercially available pharmaceutical grade；
Ratio used is weight percentage.Preparation method is industry general process conditions.
Embodiment 1：The slow-release transdermal patch formula of Isosorbide Mononitrate is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add the mixing of organic silicon pressure sensitive adhesive
Uniformly, the rubber cement of mixing is 2. applied to back lining materials, area 10000cm2, heating, drying, then covers up-protective layer, 3. on demand
Size is cut, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made.Embodiment 2：Isosorbide Mononitrate it is slow
Release transdermal patch formula as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, octadecyl alcolol are dissolved in ethyl acetate, add organic silicon pressure sensitive adhesive and be well mixed.
2. the rubber cement of mixing is applied to back lining materials, area 10000cm2, heating, drying, then covers up-protective layer,
3. size is cut on demand, packaging, that is, the transdermal patch containing Isosorbide Mononitrate is made.
Embodiment 3：The slow-release transdermal patch formula of Isosorbide Mononitrate is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add fat-soluble Acrylate pressure sensitive
Glue is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then covers up-protective layer, 3.
Size is cut on demand, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made.
Embodiment 4：The slow-release transdermal patch formula of Isosorbide Mononitrate is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add fat-soluble Acrylate pressure sensitive
Glue is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then covers up-protective layer, 3.
Size is cut on demand, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made.
Embodiment 5：The slow-release transdermal patch formula of Isosorbide Mononitrate is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, glyceryl triacetate, octadecyl alcolol are dissolved in ethyl acetate solution, add organosilicon
Class pressure sensitive adhesive is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then cover guarantor
Sheath, 3. size is cut on demand, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made.
Embodiment 6：The slow-release transdermal patch formula of Isosorbide Mononitrate is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, isopropyl myristate, octadecyl alcolol are dissolved in 50% ethanol solution, add emulsion
Type acrylate pressure sensitive adhesive is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then cover
Protective layer is covered, 3. size is cut on demand, packaging is made the slow-release transdermal patch of Isosorbide Mononitrate.
Embodiment 7：The slow-release transdermal patch formula of Isosorbide Mononitrate is as follows：
Preparation method is as follows：1. Isosorbide Mononitrate, aqueous azone, octadecyl alcolol are dissolved in 50% ethanol solution,
Add emulsion acrylic pressure sensitive adhesive to be well mixed, the rubber cement of mixing is 2. applied to back lining materials, area 10000cm2, heating is dried
It is dry, then up-protective layer is covered, 3. size is cut on demand, packaging, that is, the slow-release transdermal patch of Isosorbide Mononitrate is made.
Embodiment 8：The slow-release transdermal patch formula of Isosorbide Mononitrate is as follows：
Preparation method is as follows：1. Isosorbide Mononitrate, oleic acid, octadecyl alcolol are dissolved in ethyl acetate solution, added
Medical PSA is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then cover
Protective layer is covered, 3. size is cut on demand, packaging is made the slow-release transdermal patch containing Isosorbide Mononitrate.
6 months progress accelerated stabilities of placement are examined under the conditions of skin irritation test and 30 DEG C have been carried out to related embodiment
Examine, it is as a result as follows：
Above experimental result shows that the good best results of the stability of embodiment 4 are most preferably formula and preparation side of the invention
Method, experiment of the invention is used as laboratory sample using most preferably product of the invention.
Embodiment 9：The guinea pig in vitro skin volume of the slow-release transdermal patch of the Isosorbide Mononitrate of the present invention is passed through inside skin test
Test
The processing of guinea pig in vitro skin：400 grams or so of cavy is anesthetized with ether, back and belly wool is carefully cut off,
Cavy is put to death, skin is peeled off, subcutaneous fat is removed, refrigerated storage is standby after physiological saline is cleaned.
The transdermal measurement of guinea pig skin is determined：The sample for taking area to be 3.3005cm2 is fixed on guinea pig back skin, is used
Franz Transdermal diffusion cells carry out penetrating absorption, 32 DEG C of bath temperature, mixing speed 300rpm, reception tank volume 6ml, reception liquid
For the normal saline solution containing 0.9%NaCl.Respectively at 2, take whole samples within 6,12,24 hours, change synthermal same volume
Blank reception liquid.Sample is analyzed using high performance liquid chromatography.Result of the test shows to be shown in Table 1.
Penetrating absorption result (n=6) of the slow-release transdermal patch of the present invention of table 1 on guinea pig skin
【Explanation：Measure in daily transdermal amount=actual measurement reception liquid sample size/test specimen area per hour transdermal amount=
Daily transdermal amount/sampling test time】
Embodiment 10：The present invention the slow-release transdermal patch containing Isosorbide Mononitrate people's isolated skin it is external
Skin test is tested
The sample for taking area to be 3.3005cm2 is fixed on the in vitro skin of chest of people, is carried out using Franz Transdermal diffusion cells
Penetrating absorption, 32 DEG C of bath temperature, mixing speed 300rpm, reception tank volume 6ml, reception liquid are the physiology containing 0.9%NaCl
Saline solution.Respectively at 2, take whole samples within 6,12,24 hours, change the blank reception liquid of synthermal same volume.Sample is used
High performance liquid chromatography is analyzed.
Result of the test shows to be shown in Table 2.
Penetrating absorption results contrast (n=6) of the external application sustained release transdermal patches of the present invention of table 2 on people's isolated skin
【Explanation：Measure in daily transdermal amount=actual measurement reception liquid sample size/test specimen area transdermal amount per hour
=daily transdermal amount/sampling test time】
24 hours on cavy and human body skin of the Isosorbide Mononitrate slow-release transdermal patch of embodiments of the invention 4
Accompanying drawing 1 is shown in transdermal amount contrast：24 hour transdermal amounts of the patch of embodiment 4 on guinea pig skin are linear：Y=0.0493x+
0.0295；R2=0.9968；24 hour transdermal amounts of the patch of embodiment 4 on people's isolated skin are linear：Y=0.0378x+
0.0179；R2=0.998.
It can be seen from the results above that the slow-release transdermal patch of embodiments of the invention 4 is continuing the experiment of 24 hours
In, its active component Isosorbide Mononitrate can be kept close to constant speed, homogeneous transmission guinea pig skin and people's isolated skin.According to it
Result of the test (0.912mg/cm2d-1) inference on people's isolated skin, 22~66cm2 preparation, 24 hours transdermal amounts are about
For 20.1mg~60.2mg/ days, this concentration reached that Isosorbide Mononitrate is used for anginal dose therapeutically effective.Only need root
According to the different paster area of the setting of different dose therapeutically effectives.
Embodiment 11：The vitro release of the slow-release transdermal patch containing Isosorbide Mononitrate of the present invention is determined
Release conditions：This product 6 is taken, is shone《Chinese Pharmacopoeia》2005 editions (annex XD, the 3rd method) is carried out, with containing for 1000ml
0.9%NaCl normal saline solution is dissolution medium, 32 DEG C of temperature, 75 revs/min of rotating speed, respectively at 2,6,12,24 hours
Timing sampling 10ml, and the synthermal water of same volume is supplied immediately.Sample is detected using high performance liquid chromatography.
The slow-release transdermal patch drug release determination result of the present invention of table 3
| Sample time (h) | 2h | 6h | 12h | 24h |
| Release % | 10.3 | 30.2 | 51.8 | 90.5 |
The Isosorbide Mononitrate slow-release transdermal patch In-vitro release curves of the present invention are shown in accompanying drawing 2：Isosorbide Mononitrate
Slow-release transdermal patch vitro release is linear：Y=3.7198x+3.8253；R2=0.9904；
Embodiment 12：The pharmacodynamics test of the slow-release transdermal patch of the Isosorbide Mononitrate of the present invention
Rabbit, male, 2.0~2.6kg, 4~5 monthly ages.Harbin medical pharmaceutical university Experimental Animal Center is purchased from, logical
Single cage is raised in the suitable animal housing of wind, temperature, humidity.
1st, prepared by animal packet and model
Rabbit 42, randomly selects 7 and is only used as blank control group (A groups) before experiment, remaining 35 is only used as model group and given
Modeling：Give high fat diet (15% yolk powder, 5% lard, 80% basal feed, additional 0.5% cholesterol) totally 8 weeks, 8 weeks
End, arteria carotis communis atheromatous plaque shape is confirmed through Color doppler ultrasound, then using the method for balloon injured arteria carotis communis,
Set up stable atherosclerosis plaque block models.Modeling success rabbit is randomly divided into：Model control group (B groups), the different sorb of single nitric acid
Ester paster small dose group (C groups), Isosorbide Mononitrate paster middle dose group (D groups), Isosorbide Mononitrate paster are heavy dose of
Group (E groups), Isosorbide Mononitrate oral administration group (F groups), every group 7.Each treatment group is administered 2 weeks, in testing the 8th week and the
Take blood examination to survey within 10 weeks, and arteria carotis body surface ultrasonic examination was carried out in the 10th week.
All model groups continue in modeling successful subsequent gives high fat diet 2 weeks.Blank control group first feeds normal diet 8
In week, continue to feed normal diet 2 weeks.
2nd, medication：
Administration metering is calculated by people's rabbit dosage body surface area convert formula.Each administration group is in the (the 9th after model preparation
It is all first) drug therapy is given, C groups give low dose of Isosorbide Mononitrate paster 1 and paste/day (5cm2/ patches, specification 0.5mg/
Cm2,24 hours transdermal amount 1.5mg), D groups give middle dosage Isosorbide Mononitrate paster 1 and paste/day (3cm2/ patches, specification
1.0mg/cm2,24 hours transdermal amount 2.0mg), E groups give heavy dose of Isosorbide Mononitrate paster 1 and paste/day (3cm2/ patches, rule
Lattice 1.5mg/cm2,24 hours transdermal amount 3.0mg), successive administration 2 weeks.E groups give Isosorbide Mononitrate piece (1.09mg/kg/
D), medicine gastric infusion 2 weeks.Remaining blank control group and model control group gavage same volume physiological saline.
3rd, observation index and assay method
The measure of 3.1 rabbit anteserum NO, NOS, ET-1 contents：
Blood 4ml taken with disposable 5ml syringes Quick-acting ear edge venipuncture in the 8th week and the 10th week in experiment, be respectively placed in
In two test tubes, wherein 2ml is placed in centrifugation in a test tube, and (3000r/min, 10min, isolate serum, are placed in -20 DEG C of refrigerator guarantors
Deposit；Another 2ml is placed in centrifugation (- 4 DEG C, 4000r/min, 10min) in the l of μ containing EDTA-Na230, the μ l of Aprotinin 40 test tube and isolated
Blood plasma, -70 DEG C of refrigerators are preserved.All samples are in unified detection after collection.Operating procedure is strictly illustrated to carry out by kit.
NO, NOS are determined with enzyme linked immunosorbent assay, and ET is determined with radio immunoassay, NO kits, NOS kits, ET kits
It is purchased from Nanjing Sen Beijia bio tech ltd.
3.2 arteria carotis body surface ultrasonic examinations
Rabbit fasting 12 hours before detection, four limbs of lying on the back are fixed on experimental bench, neck preserved skin, using diasonograph along blood
Transversal scanning is made in pipe traveling, record arteria carotis communis major axis and short axis images, whether observation endarterium smooth, whether there is thicken, spot
Block portion position, Patch size and echo characteristic.Arteria carotis communis blood circumstance is shown with color Doppler, blood flow frequency spectrum, measurement is recorded
Carotid intima-media thickness (IMT), Modulus calculation method (VS), pulsating index (PI), drag index (RI), are provided to video recording
Material carries out off-line analysis.
3.3 statistical method：
Quantitative data is with mean ± standard deviationRepresent, data processing is analyzed with the statistical softwares of SPSS 17.0, group
Between compare using t examine, P ＜ 0.05 be difference it is statistically significant.
4th, result：
4.1 each group rabbit anteserum NO, NOS content
Table 1 each group rabbit anteserum NO, NOS content (x ± s)
Note:Compared ▲ P with blank control group<0.01；Compared ★ P with model group<0.01；Compared * P within 8 weeks with this group<
0.01。
As seen from Table 1, blank control group rabbit anteserum NO, NOS contents changed for 8 weeks with 10 weeks without obvious.High fat diet 8 weeks
B groups significantly reduce (P with each administration group rabbit anteserum NO, NOS content compared with normal group afterwards<0.01).On the basis of high fat diet,
Using arteria carotis sacculus expansion method reconstructed model, model control group serum NO level, NOS further substantially reduce (P<0.01), and
Each administration group has significantly rise (P than before after being administered 2 weeks<0.01).As a result show, the Atherosclerosis caused by high fat diet
Change can make endothelial injuries, serum NO level, NOS contents is substantially reduced, and aortic sac expansion can further destroy endothelial cell, promote
The unstable generation of patch, so that serum NO level, NOS are further reduced, and each administration group can be with significantly raised serum NO level, NOS
Content.
From table 1, compared with normal group, model group blood ET-1 levels are significantly raised, and ET-1/NO rises, difference has
Statistical significance (P ＜ 0.05).Each administration group significantly reduces (P than before after being administered 2 weeks<0.01).
4.2 arteria carotis body surface result of ultrasonography：
5th, analysis and summary：
Unstable angina pectoris is one of clinical manifestation of acute coronary syndrome, and the pathologic basis of coronary heart disease (CHD) is
Atherosclerosis (AS) and thrombosis.Recent studies indicate that, blood vessel inner skin cell function is the weight that CHD occurs extremely
Want one of factor.NO and ET are two kinds of important substances of endothelial cell (EC) secretion.Numerous studies show acute coronary syndrome
Function of Vascular Endothelium is damaged.Plasma Nitric Oxide (NO) concentration and Endothelin (ET) level can reflect the change of endothelial function
Change.
NO is one of most important material of human body EC synthesis, it have powerful vasodilator, suppress VSMCs propagation,
Platelet aggregation-against, adhesion and release active material effect, can prevent vasopasm and thrombosis.
ET is the most powerful contracting Angiogenesis that EC secretes, and can cause various vessel retractions, wherein coronary artery is most sensitive, may be used also
Promote blood vessel V SMCs propagation.Under physiological conditions, the NO of EC releases is dominant, can offset ET contracting blood vessel function, and ET rises can make
NO synthesis increases, and the latter increases and can suppress ET synthesis, and restricting relation is there is each other, maintains mutual dynamic to put down
Weighing apparatus, suppression vessel retraction, platelet activation, leukocyte adhesion, proliferation of smooth muscle etc., there is protective effect to cardiovascular system.
In pathological conditions, Endothelial dysfunction, the protective mechanism of endothelium is destroyed, and NO and ET releases are unbalance, and NO levels decline, ET
Secretion increase, NO/ET ratios decline, so as to promote atherosclerosis (AS) to develop, induce vasopasm, promote blood
Bolt is formed, and aggravates myocardial ischemia, and angina pectoris and myocardial infarction occurs in clinic.And NOS is the rate-limiting enzyme of NO synthesis, work as endothelial function
Not full-time, NOS translation obstacles, NOS expression density is reduced, NOS activity decreases, makes NO generation reductions.
Method of this research by applying balloon injured arteria carotis communis+weekend of High-fat diet 8 first, sets up stable dynamic
Arteries and veins plaque model, then patch is occurred experimental rupture with medicine triggering, it is copied into approximate mankind's unstable angina pectoris
Animal model.Unstable angina pectoris animal pattern is treated using the patch containing Isosorbide Mononitrate of the present invention,
The change of its blood plasma NO, NOS concentration and level of ET is observed to evaluate its influence to its Endothelial Function.
This result of study shows that the patch of the invention containing Isosorbide Mononitrate can substantially reduce Rabbits Models serum
ET content and the content of elevation of NO, and then protect vascular endothelial cell, it is of the invention containing single so as to reach preventing and treating UA effect
The low dose of patch curative effect of ISDN is suitable with oral administration.
Claims (10)
1. a kind of slow-release transdermal patch containing Isosorbide Mononitrate, it is characterised in that the slow-release transdermal patch by back sheet, contain
Medicine storage layer, anti-sticking protective layer are constituted, described pastille storage layer, containing Isosorbide Mononitrate and macromolecule sticky stuff or
Pressure sensitive adhesive, transdermal enhancer, crystallization inhibitor and solvent, wherein macromolecule sticky stuff or pressure sensitive adhesive are selected from：Water solubility third
Olefin(e) acid pressure sensitive adhesive, fat-soluble acrylate pressure sensitive adhesive, organic silicon pressure sensitive adhesive, Medical PSA are every square centimeter to contain high score
The amount of sub- sticky stuff or pressure sensitive adhesive is 1.0-30.0mg, accounts for the 70.0~95.0% of slow-release transdermal patch weight；The pastille
Also contain transdermal enhancer in storage layer, it is selected from azone, oleic acid, glyceryl triacetate, isopropyl myristate, wherein often putting down
The square centimetre of amount containing transdermal enhancer is 0-1.0mg, accounts for the 0-10.0% of slow-release transdermal patch weight；In the pastille storage layer
Also contain crystallization inhibitor octadecyl alcolol, wherein the amount every square centimeter containing crystallization inhibitor is 0.05-0.4mg, account for slow-release transdermal
The 0.3-5.0% of patch weight；Amount every square centimeter containing Isosorbide Mononitrate is 0.3~3.0mg.
2. slow-release transdermal patch according to claim 1, it is characterised in that wherein, the pressure sensitive adhesive is selected from：Fat-soluble third
Olefin(e) acid pressure sensitive adhesive, the transdermal enhancer is selected from：Azone, crystallization inhibitor is selected from：Octadecyl alcolol, solvent is selected from：Ethyl acetate；Its
In, the weight proportion of each component is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add fat-soluble acrylate pressure-sensitive adhesive and mix
Close uniform, the rubber cement of mixing is 2. applied to back lining materials, area 10000cm2, heating, drying, then up-protective layer is covered, 3. on demand
Size is wanted to cut, packaging is made the slow-release transdermal patch containing Isosorbide Mononitrate.
3. slow-release transdermal patch according to claim 2, it is characterised in that formula is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add fat-soluble acrylate pressure-sensitive adhesive and mix
Close uniform, the rubber cement of mixing is 2. applied to back lining materials, area 10000cm2, heating, drying, then cover up-protective layer, 3. on demand
Size is wanted to cut, packaging is made the slow-release transdermal patch containing Isosorbide Mononitrate；
Or
Formula is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add fat-soluble acrylate pressure-sensitive adhesive and mix
Close uniform, the rubber cement of mixing is 2. applied to back lining materials, area 10000cm2, heating, drying, then up-protective layer is covered, 3. on demand
Size is wanted to cut, packaging is made the slow-release transdermal patch containing Isosorbide Mononitrate.
4. slow-release transdermal patch according to claim 1, it is characterised in that formula is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, azone, octadecyl alcolol are dissolved in ethyl acetate, add the mixing of organic silicon pressure sensitive adhesive equal
It is even, the rubber cement of mixing is 2. applied to back lining materials, area 10000cm2, heating, drying, then cover up-protective layer, 3. chi on demand
Very little cutting, packaging, that is, be made the slow-release transdermal patch containing Isosorbide Mononitrate.
5. slow-release transdermal patch according to claim 1, it is characterised in that formula is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, octadecyl alcolol are dissolved in ethyl acetate, add organic silicon pressure sensitive adhesive and be well mixed.2. will
The rubber cement of mixing is applied to back lining materials, area 10000cm2, heating, drying, then up-protective layer is covered, 3. size is cut on demand,
Packaging, that is, be made the transdermal patch containing Isosorbide Mononitrate.
6. slow-release transdermal patch according to claim 1, it is characterised in that formula is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, glyceryl triacetate, octadecyl alcolol are dissolved in ethyl acetate solution, add organic silicon pressure
Quick glue is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then cover up-protective layer,
3. size is cut on demand, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made.
7. slow-release transdermal patch according to claim 1, it is characterised in that formula is as follows：
Preparation method is as follows：
1. Isosorbide Mononitrate, isopropyl myristate, octadecyl alcolol are dissolved in 50% ethanol solution, add emulsion-type third
Olefin(e) acid pressure sensitive adhesive is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then cover
Protective layer, 3. size is cut on demand, packaging, that is, the slow-release transdermal patch of Isosorbide Mononitrate is made.
8. slow-release transdermal patch according to claim 1, it is characterised in that formula is as follows：
Preparation method is as follows：1. Isosorbide Mononitrate, aqueous azone, octadecyl alcolol are dissolved in 50% ethanol solution, added
Emulsion acrylic pressure sensitive adhesive is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying,
Up-protective layer is covered again, 3. size is cut on demand, packaging is made the slow-release transdermal patch of Isosorbide Mononitrate.
9. slow-release transdermal patch according to claim 1, it is characterised in that formula is as follows：
Preparation method is as follows：1. Isosorbide Mononitrate, oleic acid, octadecyl alcolol are dissolved in ethyl acetate solution, added poly- different
Butylene pressure sensitive adhesive is well mixed, and the rubber cement of mixing 2. is applied into back lining materials, area 10000cm2, heating, drying, then cover
Protective layer, 3. size is cut on demand, packaging, that is, the slow-release transdermal patch containing Isosorbide Mononitrate is made.
10. the slow-release transdermal patch described in claim 1 is in treatment coronary heart diseases and angina pectoris, the medicine of myocardial infarction is prepared
Purposes.
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Application publication date: 20171107 |