CN108926549A - Rivastigmine gel emplastrum and preparation method thereof - Google Patents
Rivastigmine gel emplastrum and preparation method thereof Download PDFInfo
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- CN108926549A CN108926549A CN201811131031.5A CN201811131031A CN108926549A CN 108926549 A CN108926549 A CN 108926549A CN 201811131031 A CN201811131031 A CN 201811131031A CN 108926549 A CN108926549 A CN 108926549A
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The invention belongs to pharmacy technical fields, and in particular to a kind of Rivastigmine gel emplastrum and preparation method thereof.Rivastigmine gel emplastrum includes backing film, carry medicinal gel layer and adherent layer, the load medicinal gel layer includes active pharmaceutical ingredient and gel-type vehicle, active pharmaceutical ingredient is Rivastigmine or its pharmaceutically acceptable salt, it is characterized by: the weight ratio of the active pharmaceutical ingredient and matrix is 1-5:50-300, the matrix is prepared by the auxiliary material of following parts by weight: sodium carboxymethylcellulose 0.5-2, part neutralizes Sodium Polyacrylate 10-100, disodium ethylene diamine tetraacetate 0.1-2, PVP K30 is 5-60, carbomer 3-30, glycerol 30-80, ethyl hydroxy benzoate 0.1-0.5, Dihydroxyaluminium Aminoacetate 0.01-2, tartaric acid 0.05-0.5, vitamin e1-10, water 120-200.It the invention also discloses the preparation method of above-mentioned Rivastigmine gel emplastrum, preparing that Rivastigmine gel rubber plaster cream technique is simple, and quality is stablized using this method, sticks comfortable, Clinical Compliance is high, and it is small to the irritation of skin, it is produced on a large scale.
Description
Technical field
The invention belongs to pharmacy technical fields, and in particular to a kind of Rivastigmine gel emplastrum and preparation method thereof.
Background technique
Alzheimer's disease (Alzheimer disease, AD) is commonly called as senile dementia, is a kind of serious central nervous system
System degenerative disorders.Its pathogenesis may be the water of the hippocampus of patient, neopallium cholinacetyltranslase and acetylcholine
It is flat to substantially reduce, cortex cholinergic neuron mediator dysfunction.Its clinical manifestation mainly has memory disorders, cognitive disorder and essence
Refreshing behavior disorder.With the arrival of Chinese society's aging, elderly population number is increasing, and the old man for suffering from senile dementia is also increasingly
It is more.Various symptoms such as memory loss, retardation of thinking, behavior disorder have seriously affected the work of Alzheimer's
Work, family and social relationships.Currently, Rivastigmine is the active drug for treating alzheimer's disease.
Currently, the dosage form of the Rivastigmine listed has oral preparation (capsule) and preparation capable of permeating skin (transdermal patch), thoroughly
Skin patch, which refers to, to be affixed on skin, and drug percutaneous skin absorbs the laminar preparation for generating general action or local therapeutic effects, because
This is not influenced without liver first-pass effect by gastric emptying rate etc..But transdermal patch is since listing in 2007, although user
Just, but skin irritation is larger, and patient compliance is poor.Since the medicine needs to be used for a long time, therefore it is badly in need of developing and sticks comfortably
Preparation capable of permeating skin.
Gel ointment is one kind of emplastrum, is made of back sheet, paste layer and anti-stick layer three parts.Back sheet, mainly
As the carrier of lotion, non-woven fabrics, spun rayon cloth etc. are commonly used；Paste layer, i.e. matrix and main ingredient part generate certain in sticking
Adhesion be allowed to skin be in close contact, to reach therapeutic purposes；Anti-stick layer play a part of protect lotion, commonly use anti-sticker,
Plastic film, hard gauze etc..Gel ointment is after being mixed by main ingredient and matrix, to be coated on back lining materials and be made, therefore base
The formula of matter is the core content of gel ointment research.
Summary of the invention
The primary purpose of the present invention is that provide a kind of stability it is good, without the good card of skin irritation, transdermal release performance
Ba Lating gel emplastrum.
To achieve the above object, the technical solution adopted by the present invention is that:
A kind of Rivastigmine gel emplastrum, including backing film, carry medicinal gel layer and adherent layer, the load medicinal gel layer and include
Active pharmaceutical ingredient and gel-type vehicle, active pharmaceutical ingredient are Rivastigmine or its pharmaceutically acceptable salt, it is characterised in that:
The weight ratio of the active pharmaceutical ingredient and matrix is 1-5:50-300, and the matrix is prepared by the auxiliary material of following parts by weight
Obtain: sodium carboxymethylcellulose 0.5-2, part neutralize Sodium Polyacrylate 10-100, disodium ethylene diamine tetraacetate 0.1-2, poly- dimension
Ketone K30 be 5-60, carbomer 3-30, glycerol 30-80, ethyl hydroxy benzoate 0.1-0.5, Dihydroxyaluminium Aminoacetate 0.01-2, tartaric acid 0.05-0.5,
Vitamin E 1-10, water 120-200.
The solution of the present invention increases using carbomer, PVP K30, sodium carboxymethylcellulose and Sodium Polyacrylate as adhesive
The strong stability of system, improves the glossiness of product, holds viscous force, takes off patch property, matrix residual and skin tracing ability repeatedly；
Glycerol is in addition to moisture-keeping function, and acceptable and carbomer is with Hydrogenbond, to further increase the stability of matrix；Vitamin E
It is liposoluble vitamin, skin absorption of drugs can be promoted；Ethyl hydroxy benzoate can effectively inhibit gel emplastrum mould growth；
As crosslinking agent, disodium ethylene diamine tetraacetate and tartaric acid, as cross-linking regulator, gel emplastrum can be effectively ensured in Dihydroxyaluminium Aminoacetate
Whole cohesive force, and then ensure that gel emplastrum is able to machine-shaping.
Preferably, the matrix is prepared by the auxiliary material of following parts by weight: sodium carboxymethylcellulose
0.5-1, part neutralize Sodium Polyacrylate 10-50, disodium ethylene diamine tetraacetate 0.1-1, PVP K30 5-30, carbomer 3-
15, glycerol 30-100, ethyl hydroxy benzoate 0.1-0.3, Dihydroxyaluminium Aminoacetate 0.01-1, tartaric acid 0.05-0.2, vitamin e1-5, water 120-
180。
It is highly preferred that the active pharmaceutical ingredient and matrix are by following parts by weight are as follows: Rivastigmine 1, carboxymethyl cellulose
Plain sodium 0.8, part neutralize Sodium Polyacrylate 15, disodium ethylene diamine tetraacetate 0.2, PVP K30 10, carbomer 15, glycerol
40, ethyl hydroxy benzoate 0.1, Dihydroxyaluminium Aminoacetate 0.2, tartaric acid 0.1, vitamin E 2, water 120.
Another object of the present invention be to provide a kind of simple production process, it is at low cost, can be with the card of large-scale production
The preparation method of Ba Lating gel emplastrum, comprising the following steps:
S1 carbomer, sodium carboxymethylcellulose and PVP K30) are taken, be mixed with water to obtain components I；
S2 Sodium Polyacrylate, glycerol, vitamin E) are taken and Rivastigmine is added to stir evenly, obtains compositionⅱ；
S3 disodium ethylene diamine tetraacetate and Dihydroxyaluminium Aminoacetate) are weighed, is mixed with water, component III is obtained；
S4) water intaking is appropriate, adds tartaric acid stirring and dissolving, obtains component IV；
S5 ethyl hydroxy benzoate) is weighed, is dissolved with ethanol in proper amount, is added in compositionⅱ, components I, III, IV are sequentially added, it is close
Stirring is closed, coating, compound, cutting are to get product.
The Rivastigmine gel emplastrum moulding process prepared using method disclosed by the invention is simple and easy to do, drug and matrix
Uniform lotion can be obtained after material mixing, Rivastigmine gel emplastrum can be obtained in coated, compound, cutting, can scale
Metaplasia produces.
Preferably, in the step S1, carbomer, sodium carboxymethylcellulose and PVP K30 first use water respectively
It is sufficiently swollen and stirs evenly, then three is uniformly mixed to obtain components I.In the step S2, Sodium Polyacrylate is taken, it is abundant that glycerol is added
Be stirred until homogeneous, vitamin E added to stir evenly, then plus Rivastigmine stir evenly, obtain compositionⅱ.It is closed in the step S5 to stir
Mix 10-20min.It is 10 square centimeters, dosage 16.2-19.8mg that administration area is cut into the step S5, and paste containing amount is
1.2-1.4g/10 square centimeter.
Experiment discovery, Rivastigmine not only have excellent stability and release performance in the gel-type vehicle, but also interior
Poly- power is stronger；Rivastigmine dosage needed for capable of carrying percutaneous effectively treatment 24 hours, realize 24 hours effectively, stablize, hold
Continuous administration；It is found using transdermal test in vitro release experiment, continues 24 hours accumulation infiltration capacities up to 3712 μ g/cm through rat skin2,
The transdermal penetration rates of drug are high；Rivastigmine gel emplastrum obtained is singly miscellaneous in 6 months accelerated stability tests to be below
0.20%, it is always miscellaneous to be lower than 1%；Patch can keep good gas permeability and penetrability after sticking skin, therefore can effectively reduce
To the irritation of skin；Initial bonding strength is stronger, up to 28-30 steel ball.
Have the advantages of the following aspects using Rivastigmine gel emplastrum prepared by the above method:
(1) it sticks comfortable: compared with the transdermal plaster of rivastigmine of the prior art, Rivastigmine gel emplastrum of the invention
In the moisture that contains it is more, therefore while using, can make the cuticula of human skin be easy softening, and skin-friendly is good, sticks comfortable；
(2) small to the irritation of skin: pressure sensitive adhesive poor air permeability used in prior art preparation transdermal plaster of rivastigmine,
Easily cause skin allergy or stimulation, in contrast, matrix used in Rivastigmine gel emplastrum of the invention is mostly macromolecule water
Product is effectively reduced to skin irritation in soluble materials, to improve the compliance of patient；
(3) initial bonding strength is stronger: Rivastigmine gel emplastrum disclosed by the invention can cling 28-30 steel ball, not only stick
Comfortably, it and sticks securely.
It (4) can be with large-scale production: using the Rivastigmine gel emplastrum moulding process of method disclosed by the invention preparation
It is simple and easy to do, it is produced on a large scale.Specifically, drug can obtain uniform lotion after mixing with host material, it is coated, multiple
Splitting or integrating, which is cut, can be obtained Rivastigmine gel emplastrum.
Detailed description of the invention
Fig. 1 is the In-vitro release curves figure of embodiment 1-5 and comparative example 1；
Fig. 2 is the transdermal test in vitro curve graph of embodiment 1-5 and comparative example 1.
Specific embodiment
1-5 is further described technical solution disclosed by the invention with reference to embodiments.
Embodiment 1: the preparation of Rivastigmine gel emplastrum
(1) 3 parts of carbomer, 0.5 part of sodium carboxymethylcellulose and 5 parts of PVP K30 are weighed respectively, and suitable quantity of water is added and fills
Point swelling, stirs evenly, remixes uniform components I；
(2) 10 parts of Sodium Polyacrylate are weighed, glycerol is added and is stirred well to uniformly, vitamin e1 part is added to stir evenly, then
Add 1 part of Rivastigmine, stirs evenly, obtain compositionⅱ；
(3) 0.1 part and 0.1 part of Dihydroxyaluminium Aminoacetate of disodium ethylene diamine tetraacetate is weighed, is mixed with water, obtains component III；
(4) water intaking is appropriate, adds 0.05 part of tartaric acid, stirring and dissolving obtains component IV；
(5) weigh 0.1 part of ethyl hydroxy benzoate, with a small amount of ethyl alcohol dissolve, be added in compositionⅱ, sequentially add components I, III,
IV, closed stirring 10 minutes, coating, compound, cutting are to get product.It is detected through initial bonding strength, which can stick
Firmly No. 28 steel balls.
Embodiment 2: the preparation of Rivastigmine gel emplastrum
(1) 10 parts of carbomer, 1 part of sodium carboxymethylcellulose and 15 parts of PVP K30 are weighed respectively, and suitable quantity of water is added and fills
Point swelling, stirs evenly, remixes uniform components I；
(2) 30 parts of Sodium Polyacrylate are weighed, glycerol is added and is stirred well to uniformly, adds 3 parts of vitamin E to stir evenly, then
Add 3 parts of Rivastigmine, stirs evenly, obtain compositionⅱ；
(3) 0.5 part and 0.3 part of Dihydroxyaluminium Aminoacetate of disodium ethylene diamine tetraacetate is weighed, is mixed with water, obtains component III；
(4) water intaking is appropriate, adds 0.2 part of tartaric acid, stirring and dissolving obtains component IV；
(5) weigh 0.3 part of ethyl hydroxy benzoate, with a small amount of ethyl alcohol dissolve, be added in compositionⅱ, sequentially add components I, III,
IV, closed stirring 20 minutes, coating, compound, cutting are to get product.It is detected through initial bonding strength, which can stick
Firmly No. 30 steel balls.
Embodiment 3: the preparation of Rivastigmine gel emplastrum
(1) 5 parts of carbomer, 0.5 part of sodium carboxymethylcellulose and 10 parts of PVP K30 are weighed respectively, and suitable quantity of water is added and fills
Point swelling, stirs evenly, remixes uniform components I；
(2) 20 parts of Sodium Polyacrylate are weighed, glycerol is added and is stirred well to uniformly, vitamin E2 part is added to stir evenly, then
Add 2 parts of Rivastigmine, stirs evenly, obtain compositionⅱ；
(3) it weighs 0.2 part of disodium ethylene diamine tetraacetate and 0.2 part of Dihydroxyaluminium Aminoacetate appropriate, be mixed with water, obtain component III；
(4) water intaking is appropriate, adds 0.1 part of tartaric acid, stirring and dissolving obtains component IV；
(5) weigh 0.2 part of ethyl hydroxy benzoate, with a small amount of ethyl alcohol dissolve, be added in compositionⅱ, sequentially add components I, III,
IV, closed stirring 15 minutes, coating, compound, cutting are to get product.It is detected through initial bonding strength, which can stick
Firmly No. 28 steel balls.
Embodiment 4: the preparation of Rivastigmine gel emplastrum
(1) 7 parts of carbomer, 0.6 part of sodium carboxymethylcellulose and 12 parts of PVP K30 are weighed respectively, and suitable quantity of water is added and fills
Point swelling, stirs evenly, remixes uniform components I；
(2) 22 parts of Sodium Polyacrylate are weighed, glycerol is added and is stirred well to uniformly, adds 3 parts of vitamin E to stir evenly, then
Add 2 parts of Rivastigmine, stirs evenly, obtain compositionⅱ；
(3) it weighs 0.3 part of disodium ethylene diamine tetraacetate and 0.3 part of Dihydroxyaluminium Aminoacetate appropriate, be mixed with water, obtain component III；
(4) water intaking is appropriate, adds 0.1 part of tartaric acid, stirring and dissolving obtains component IV；
(5) weigh 0.2 part of ethyl hydroxy benzoate, with a small amount of ethyl alcohol dissolve, be added in compositionⅱ, sequentially add components I, III,
IV, closed stirring 15 minutes, coating, compound, cutting are to get product.It is detected through initial bonding strength, which can stick
Firmly No. 28 steel balls.
Embodiment 5: the preparation of Rivastigmine gel emplastrum
(1) 12 parts of carbomer, 0.8 part of sodium carboxymethylcellulose and 20 parts of PVP K30 are weighed respectively, and suitable quantity of water is added
Sufficiently swelling, stirs evenly, and remixes uniform components I；
(2) 40 parts of Sodium Polyacrylate are weighed, glycerol is added and is stirred well to uniformly, adds 4 parts of vitamin E to stir evenly, then
Add 4 parts of Rivastigmine, stirs evenly, obtain compositionⅱ；
(3) it weighs 0.8 part of disodium ethylene diamine tetraacetate and 0.8 part of Dihydroxyaluminium Aminoacetate appropriate, be mixed with water, obtain component III；
(4) water intaking is appropriate, adds 0.15 part of tartaric acid, stirring and dissolving obtains component IV；
(5) weigh 0.3 part of ethyl hydroxy benzoate, with a small amount of ethyl alcohol dissolve, be added in compositionⅱ, sequentially add components I, III,
IV, closed stirring 15 minutes, coating, compound, cutting are to get product.It is detected through initial bonding strength, which can stick
Firmly No. 30 steel balls.
Comparative example 1: commercially available Rivastigmine patch is chosen as comparative example, the product name of the commercial product is
EXELON, article No. 4546B, EXP JUL 2018, specification 9mg/5cm2And 18mg/10cm2。
The performance test comparative test of embodiment sample and comparative example product:
One, stability test
Rivastigmine percutaneous plaster in the Rivastigmine gel emplastrum and comparative example 1 of embodiment 1-5, which is put into temperature, is
40 DEG C, relative humidity is in 75% stability test case, detection Rivastigmine content and impurity content, is as a result shown in after 6 months
Table 1-1 and table 1-2.
Table 1-1 Rivastigmine gel emplastrum accelerates 6 months Rivastigmine contents
Table 1-2 Rivastigmine gel emplastrum accelerates 6 months impurity contents
As shown in Table 1, Rivastigmine gel emplastrum obtained all has higher stability in embodiment 1-5.This explanation:
Rivastigmine stability with higher in gel-type vehicle of the invention, meets national regulations.
Two, mechanics evaluation is tested
(1) initial bonding strength inspection: by the gel emplastrum of embodiment 1-5, being cut into 50mm × 100mm size, by 2015 years versions
" Chinese Pharmacopoeia " four adhesive forces measure the first method and are measured, and record the maximum steel ball number that can be clung, the results are shown in Table 2.
The detection of 2 Rivastigmine gel emplastrum initial bonding strength of table
| Sample | Initial bonding strength/steel ball number |
| Embodiment 1 | 28 |
| Embodiment 2 | 30 |
| Embodiment 3 | 28 |
| Embodiment 4 | 28 |
| Embodiment 5 | 30 |
(2) holding power is tested: by the patch in the gel emplastrum and comparative example 1 of embodiment 1-5, be cut into 50mm ×
100mm size is attached at respectively on the clean stainless steel plate placed vertically, first rolls 3 back and forth on each emplastrum with the roller of 2kg
It is secondary, then 200g counterweight is hung below emplastrum, lead is parallel with gravity direction, and record emplastrum completely falls off required
Time the results are shown in Table 3.
The detection of 3 Rivastigmine gel emplastrum holding power of table
| Sample | Holding power/min |
| Comparative example 1 | 79.52 |
| Embodiment 1 | 43.56 |
| Embodiment 2 | 47.78 |
| Embodiment 3 | 44.53 |
| Embodiment 4 | 45.48 |
| Embodiment 5 | 46.82 |
From table 2,3: Rivastigmine gel emplastrum obtained all has preferable mechanical property in embodiment 1-5.This
Illustrate: Rivastigmine has preferable mechanical property in gel-type vehicle of the invention, specifically, initial bonding strength is strong, and when continuing
Between it is longer, fully meet the requirement of clinical application.
Three, vitro release is tested
1, instrument and reagent
Instrument: TK-12A percutaneous dispersion test instrument；2695/2998 high performance liquid chromatograph of Waters e.
Reagent: physiological saline；Methanol (chromatographic grade, SIGAMA)；Disodium hydrogen phosphate, triethylamine (analysis is pure)；Liquor epinephrinae bitartratis ophthalmicus
Rivastigmine reference substance (lot number Y0001516)；Rivastigmine gel emplastrum (An Keyuliang minister in ancient times pharmaceutcal corporation, Ltd, lot number point
Not are as follows: 20180201,20180202,20180203,20180204,20180205)；Rivastigmine patch (Novartis Co., Ltd, commodity
Entitled EXELON, article No. 4546B, EXP JUL 2018).
2, method and result
The foundation of 2.1 vitro release experimental methods
Experimental provision uses improved Franz diffusing cells method, which is involuted by upper and lower two tubular glass tubes, presss from both sides
Dialysis membrane therebetween will be divided into two Room above and below, and upper chamber is diffuser casing, and lower room is receiving chamber, be connected in the side of receiving chamber
For sample introduction, sampling and the probe tube for excluding bubble.Diffusion cell volume is 6.5ml, and effective diffusion area is 2.2cm2.It takes respectively
Patch in gel emplastrum and comparative example 1 in embodiment 1-5, is attached on dialysis membrane；Physiological saline is filled into receiving chamber, is arranged
Bubble removing, bath temperature are 32 ± 0.2 DEG C, add stirrer constant temperature to stir, revolving speed 300r/min.After experiment starts
0.5,1,2,4,8,12,200 μ l are sampled from receiving chamber with microsyringe for 24 hours, while respectively adding 32 ± 0.2 DEG C of same volume preheatings
Physiological saline, physiological saline filter in advance and ultrasonic degassing steep.
Samples taken is respectively placed in 5ml volumetric flask, add methanol -0.05M disodium hydrogen phosphate-triethylamine (50:50:
0.02) it is settled to scale, is shaken up, filters, takes subsequent filtrate as assay test solution.
Precision weighs liquor epinephrinae bitartratis ophthalmicus Rivastigmine reference substance 6.34mg, is placed in 10ml volumetric flask, with methanol -0.05M phosphorus
Sour disodium hydrogen-triethylamine (50:50:0.02) is settled to scale to get reference substance solution.
The foundation of Rivastigmine analysis method in 2.2 release in vitro liquid
Using Thermo ODSHYPERSIL chromatographic column (5 μm of partial size, 4 × 250mm of size), with methanol -0.05M phosphoric acid hydrogen
Disodium-triethylamine (50:50:0.02) is mobile phase；Detection wavelength is 214nm, and column temperature is room temperature (21~26 DEG C), and flow velocity is
1ml/min.Precision draws each 10 μ l of test solution and control solution, is injected separately into high performance liquid chromatograph, measures, and
It calculates preparation (%).It is mapped with preparation (%) to release time (t), draws In-vitro release curves, as a result such as
Shown in Fig. 1.
Four, Ligustrazine hydrochloride is tested
1. instrument and reagent
Instrument: TK-12A type percutaneous dispersion test instrument；2695/2998 high performance liquid chromatograph of Waters e.
Reagent: physiological saline；Methanol (chromatographic grade, SIGAMA)；Disodium hydrogen phosphate, triethylamine (analysis is pure)；Liquor epinephrinae bitartratis ophthalmicus
Rivastigmine reference substance；Rivastigmine gel emplastrum (An Keyuliang minister in ancient times pharmaceutcal corporation, Ltd, lot number is respectively as follows: 20180201,
20180202,20180203,20180204,20180205)；Rivastigmine patch (Novartis Co., Ltd, trade name EXELON, goods
Number be 4546B, EXP JUL 2018).
2, method and result
The foundation of 2.1 transdermal permeation in vitro methods
Experimental provision uses improved Franz diffusing cells method, which is involuted by upper and lower two tubular glass tubes, presss from both sides
Mouse skin therebetween will be divided into two Room above and below, and upper chamber is diffuser casing, and lower room is receiving chamber, mouse skin stratum corneum side towards diffuser casing,
It is connected in the side of receiving chamber for sample introduction, sampling and the probe tube for excluding bubble.Diffusion cell volume is 6.5ml, is effectively expanded
Dissipating area is 2.2cm2.Patch in gel emplastrum and comparative example 1 in Example 1-5 respectively, is attached at mouse skin stratum corneum side
On；Physiological saline is filled into receiving chamber, excludes bubble, and bath temperature is 32 ± 0.2 DEG C, adds stirrer constant temperature to stir, revolving speed
For 300r/min.0.5,1,2,4,8,12 after experiment starts, 200 μ l are sampled from receiving chamber with microsyringe for 24 hours, together
When respectively add 32 ± 0.2 DEG C of same volume preheating physiological saline, physiological saline filter in advance and ultrasonic degassing bubble.
Samples taken is respectively placed in 5ml volumetric flask, add methanol -0.05M disodium hydrogen phosphate-triethylamine (50:50:
0.02) it is settled to scale, is shaken up, filters, takes subsequent filtrate as assay test solution.
Precision weighs liquor epinephrinae bitartratis ophthalmicus Rivastigmine reference substance 6.34mg, is placed in 10ml volumetric flask, with methanol -0.05M phosphorus
Sour disodium hydrogen-triethylamine (50:50:0.02) is settled to scale to get reference substance solution.
The foundation of Rivastigmine analysis method in 2.2 Cutaneous permeation liquid
Using Thermo ODSHYPERSIL chromatographic column (5 μm of partial size, 4 × 250mm of size), with methanol -0.05M phosphoric acid hydrogen
Disodium-triethylamine (50:50:0.02) is mobile phase；Detection wavelength is 214nm, and column temperature is room temperature (21~26 DEG C), and flow velocity is
1ml/min.Precision draws each 10 μ l of test solution and control solution, is injected separately into high performance liquid chromatograph, measures, and
It calculates preparation (%).It is mapped with preparation (%) to release time (t), draws transdermal test in vitro curve, as a result such as
Shown in Fig. 2.
From Fig. 1-2: Rivastigmine gel emplastrum obtained all has good percutaneous release property in embodiment 1-5
Can, it is suitable with the Rivastigmine patch of comparative example 1.This explanation: Rivastigmine has good in gel-type vehicle of the invention
Percutaneous release performance.
Five, the irritation test of Rivastigmine gel emplastrum of the invention to skin
Healthy rabbits (2.3 ± 0.2kg) 12 are taken, half male and half female is divided into intact skin group and damaged skin group, is being administered
First 48 hours, back part of animal vertebra two sides are lost hair or feathers with 6% sodium sulfide solution, every lateral area is about 50cm2, 24 hours after unhairing
It is injured due to unhairing to check whether skin of unhairing has, the damaged skin of rabbit is produced as follows: unhairing being sterilized skin with scalpel
Skin scratches, and is degree with oozing of blood, and the damaged degree of control left and right sides skin is consistent substantially.
Test is using androgynous left and right Self-control method: giving Rivastigmine gel emplastrum and blank respectively in left and right sides unhairing area
Control is smeared once, successive administration 7 days daily；Respectively stop administration after 1,24,48,72 hour observation medicine-feeding part whether there is or not
Situations such as erythema and oedema, while paying attention to observing whether medicine-feeding part has situations such as pigmentation, blutpunkte, pachylosis.Knot
It after fruit shows Rivastigmine gel emplastrum successive administration 7 days, is observed in 72 hours, rabbit intact skin group and damaged skin
Group is showed no the irritative responses such as erythema, oedema.
Claims (8)
1. a kind of Rivastigmine gel emplastrum, including backing film, load medicinal gel layer and adherent layer, the load medicinal gel layer includes medicine
Object active constituent and gel-type vehicle, active pharmaceutical ingredient are Rivastigmine or its pharmaceutically acceptable salt, it is characterised in that: institute
The weight ratio for stating active pharmaceutical ingredient and matrix is 1-5:50-300, and the matrix is prepared by the auxiliary material of following parts by weight
Arrive: sodium carboxymethylcellulose 0.5-2, part neutralize Sodium Polyacrylate 10-100, disodium ethylene diamine tetraacetate 0.1-2, povidone
K30 is 5-60, carbomer 3-30, glycerol 30-80, ethyl hydroxy benzoate 0.1-0.5, Dihydroxyaluminium Aminoacetate 0.01-2, tartaric acid 0.05-0.5, ties up
Raw element E1-10, water 120-200.
2. Rivastigmine gel emplastrum according to claim 1, it is characterised in that: the matrix is by following parts by weight
Several auxiliary materials are prepared: sodium carboxymethylcellulose 0.5-1, part neutralize Sodium Polyacrylate 10-50, disodium ethylene diamine tetraacetate
0.1-1, PVP K30 5-30, carbomer 3-15, glycerol 30-100, ethyl hydroxy benzoate 0.1-0.3, Dihydroxyaluminium Aminoacetate 0.01-1, winestone
Sour 0.05-0.2, vitamin e1-5, water 120-180.
3. Rivastigmine gel emplastrum according to claim 1 to 2, it is characterised in that: the active pharmaceutical ingredient and matrix
By following parts by weight are as follows: Rivastigmine 1, sodium carboxymethylcellulose 0.8, part neutralize Sodium Polyacrylate 15, ethylenediamine tetrem
Acid disodium 0.2, PVP K30 10, carbomer 15, glycerol 40, ethyl hydroxy benzoate 0.1, Dihydroxyaluminium Aminoacetate 0.2, tartaric acid 0.1, dimension life
Plain E 2, water 120.
4. the preparation method of Rivastigmine gel emplastrum according to any one of claim 1-3, comprising the following steps:
S1 carbomer, sodium carboxymethylcellulose and PVP K30) are taken, be mixed with water to obtain components I；
S2 Sodium Polyacrylate, glycerol, vitamin E) are taken and Rivastigmine is added to stir evenly, obtains compositionⅱ；
S3 disodium ethylene diamine tetraacetate and Dihydroxyaluminium Aminoacetate) are weighed, is mixed with water, component III is obtained；
S4) water intaking is appropriate, adds tartaric acid stirring and dissolving, obtains component IV；
S5 ethyl hydroxy benzoate) is weighed, is dissolved with ethanol in proper amount, is added in compositionⅱ, components I, III, IV are sequentially added, it is closed to stir
It mixes, coating, compound, cutting are to get product.
5. the preparation method of Rivastigmine gel emplastrum according to claim 4, it is characterised in that: close in the step S5
Close stirring 10-20 minutes.
6. the preparation method of Rivastigmine gel emplastrum according to claim 4, it is characterised in that: divide in the step S5
Being cut into administration area is 10 square centimeters, dosage 16.2-19.8mg, and paste containing amount is 1.2-1.4g/10 square centimeters.
7. the preparation method of Rivastigmine gel emplastrum according to claim 4, it is characterised in that: in the step S1,
Carbomer, sodium carboxymethylcellulose and PVP K30 are first sufficiently swollen and are stirred evenly with water respectively, then three is uniformly mixed to obtain group
Divide I.
8. the preparation method of Rivastigmine gel emplastrum according to claim 4, it is characterised in that: in the step S2,
Take Sodium Polyacrylate, glycerol be added and is stirred well to uniformly, vitamin E is added to stir evenly, then plus Rivastigmine stir evenly, obtain
Compositionⅱ.
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