CN108451934A - A kind of transdermal patch and preparation method thereof containing rotigotine - Google Patents
A kind of transdermal patch and preparation method thereof containing rotigotine Download PDFInfo
- Publication number
- CN108451934A CN108451934A CN201710588689.8A CN201710588689A CN108451934A CN 108451934 A CN108451934 A CN 108451934A CN 201710588689 A CN201710588689 A CN 201710588689A CN 108451934 A CN108451934 A CN 108451934A
- Authority
- CN
- China
- Prior art keywords
- self
- adhesive matrix
- composition
- rotigotine
- patch
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
Abstract
The invention discloses a kind of compositions being used to prepare the transdermal patch containing rotigotine, the transdermal patch and preparation method thereof containing rotigotine, and its composition includes a effective amount of rotigotine and self-adhesive matrix, and the self-adhesive matrix includes following ingredient：Medical PSA and colloid softening agent.Transdermal patch containing rotigotine prepared by the present invention, use Medical PSA, its C H skeleton is longer and straight, and only end group has unsaturated bond, since double bond is few, response location is few, therefore the transdermal patch containing rotigotine prepared by the present invention is highly stable, weatherability, heat resistance and ageing resistance are good, and at low cost, material is easy to get, and operability is strong.It is also added with colloid softening agent, the stability of patch is improved, avoids active constituents of medicine from the precipitation in preparation；Further, it is added with viscous force conditioning agent, makes transdermal patch that there is preferable permeability.
Description
Technical field
The invention belongs to prepare the technical field for the treatment of Parkinsonism drug, and in particular to one kind is containing sieve for height
The transdermal patch in spit of fland and preparation method thereof.
Background technology
Parkinson's disease is a kind of disease mainly broken out in person in middle and old age, it equally influences male and female.Parkinson
The highest incidence of family name's disease appears in the crowd of 70 years old or more age group, and there are op parkinson's by the 1.5-2.5% of these crowds
Disease.Average age when morbidity is 58-62 Sui, develops into the most patients of Parkinson's disease between 50-79 Sui.Only in U.S.
State just has about 800, and 000 people suffers from Parkinson's disease.It is more that the poverty of movement of Parkinson's disease early stage can trace back to release black substance
The degeneration of the cell of bar amine.This deterioration of neurons can generate defect in the dopamine-pathway of connection black substance and corpus straitum.
Rotigotine is a kind of one of which dopamine-receptor stimulant for treating Parkinsonism.Sieve is for height
Spit of fland is compound (-) -5, and the world of 6,7,8- tetrahydrochysene -6- [propyl-[2- (2- thienyls) ethyl]-amino] -1- naphthols is non-specially
There is title (INN).Currently, having the various transdermal therapeutic systems (TTS) for giving rotigotine, as WO99/49852 is described
A kind of Transdermal Therapeutic System containing rotigotine based on acrylate or siloxanes.Adhesive used in the system
For acrylate or siloxanes, they form the system using single adhesive with active medicine respectively.Wherein with acrylate
For the system of adhesive composition, drug release rate is low；And the system being made of adhesive with siloxanes, drug load
Smaller, the drug initial release amount of product is relatively low.
WO2002/089778 describes a kind of transdermal therapeutic system based on siloxanes and is used to prepare anti-Parkinson's disease
Medicament purposes.The transdermal therapeutic system contains rotigotine as active constituent.But the drug release rate of the system
Relatively low, the in particular up to overlong time of effective dose, leading to it, there are probelem in two aspects：1. effective in order to reach
Blood concentration, the transdermal patch must be replaced frequently, for example 24 hours even shorter times just need replacing once, unfavorable in this way
In play patch facilitate patient to use the advantages of；2. the penetrating amount of the starting of the transdermal patch is relatively low, so as to cause from sticking
Patch is long to efficacy time is played, and often results in the delay of the Patient controlled state of an illness in this way.In short, rotigotine is existing
Skin penetration rate is low in skin treatment system, and stability is poor, and good therapeutic effect is not achieved.
Invention content
The purpose of the present invention is to provide a kind of compositions being used to prepare the transdermal patch containing rotigotine, to solve
Certainly current rotigotine is low in the low middle skin penetration rate of penetrance of acrylic pressure-sensitive adhesivee, and therapeutic effect and stability is not achieved
The technical problem of difference.Another object of the present invention is to provide a kind of transdermal patch and preparation method thereof containing rotigotine.
To achieve the above object, the present invention use technical solution below for：
A kind of composition being used to prepare the transdermal patch containing rotigotine comprising a effective amount of rotigotine and from
Adhesive matrix, the self-adhesive matrix include Medical PSA and colloid softening agent.
Composition as above, it is preferable that the Medical PSA is including being 1 by weight proportion:10~10:1 point
The low molecular polyisobutylene and viscous force tune that the polyphosphazene polymer isobutene and molecular weight that son amount is 450,000~2,100,000 are 1000~450,000
Save agent, the colloid softening agent be atoleine, light liquid paraffin, low molecular weight polyisobutene, lanolin, lubricant grease,
Preferred liquid paraffin, light liquid paraffin, more preferable light liquid paraffin, the viscous force conditioning agent are selected from：Polybutene, low molecule
The substance of polybutene, acroleic acid binding agent, acetic acid/vinyl acetate co-polymer (EVA) and other adjustable viscous forces, wherein it is preferred that
Polybutene, low molecular weight polycaprolactone butylene, more preferable low molecular weight polycaprolactone butylene, the low molecular weight polycaprolactone butylene molecular weight is 500~1500, described
The dosage of viscous force conditioning agent is that the weight ratio of the Medical PSA is less than 55%, preferably 5~44%.
Composition as above, it is preferable that the polyisobutene Type of Collective object is in the weight ratio of the self-adhesive matrix
20%~99%, preferably 40%~77%；The colloid softening agent the self-adhesive matrix weight ratio be less than 55%, it is excellent
Choosing is less than 44%, is further preferably no larger than 33%, more preferable 1~22%；The weight of the rotigotine in the composition
Than being 5%~20%, preferably 8%~15%, the dosage of the viscous force conditioning agent is the weight of the polyisobutene Type of Collective object
Than being less than 55%, preferably 5~44%.
Composition as above, it is preferable that the self-adhesive matrix further includes having silicone pressure-sensitive adhesive or acrylic pressure-sensitive adhesivee,
The mass percentage of the silicone pressure-sensitive adhesive or acrylic pressure-sensitive adhesivee in the self-adhesive matrix be 0~20%, preferably 0~
15%.
Composition as above, it is preferable that the self-adhesive matrix further includes penetration enhancer, and the penetration enhancer is in institute
State self-adhesive matrix weight ratio be 0%~15%, preferably 0.5%~7%, the penetration enhancer can be Laurocapram and
Its analog, such as Azone；Long-chain is saturated or unsaturated fatty acid such as oleic acid, lauric acid etc..
Composition as above, it is preferable that the self-adhesive matrix further includes surfactant substance, such as tween, sapn,
Sldium lauryl sulfate etc.；Alcohols and polyalcohols such as propylene glycol, glycerine etc., amine and amides, such as urea.
Composition as above, it is preferable that the self-adhesive matrix further includes solvent misture, refers to a kind of pressure-sensitive for improving
The substance of the interfacial bond power and plasticising performance of glue, can be used for adjusting the viscous force of patch, and the tackifying resin is the derivative of rosin
Object, cyclopentadiene or isoprene, in the weight ratio 5~25% of the self-adhesive matrix.
Composition as above, it is preferable that the self-adhesive matrix further includes stabilizer, and the stabilizer is in the tack
The weight ratio of matrix is 0%-15%, preferably 0.5%-7%, and the stabilizer is polyvinylpyrrolidone class, poloxamer, poly-
Glycols.
Composition as above, it is preferable that the self-adhesive matrix further includes having other fillers, and other fillers exist
The weight ratio of the self-adhesive matrix is 0%~15%, preferably 0.5%~7%, and other fillers are starch, titanium dioxide
Silicon, colloidal silicon dioxide or superfine silica gel powder.
Composition as above, it is preferable that the self-adhesive matrix layer further includes polyphenoils, and the antioxygen turns to Vitamin C
The mixture of one or more of sour palmitate, sodium pyrosulfite, DL-a- tocopherols or dibutyl hydroxy toluene, it is described
The dosage of polyphenoils is the 0.01%~2% of the self-adhesive matrix layer.
A kind of transdermal patch containing rotigotine, contains composition as described above.
Specifically, a kind of supporting layer of the composition chemically reactive including described in composition as described above, discord and
The protective film or release film that must be removed before one use.
Release film for patch of the present invention plays the role of protecting adhesive phase, in patch before use, release film is shelled
From getting off, patch is pasted on position used.The thickness of wherein release film is generally 50~150 μm, and material is generally coated with spy
The non-permeable material of different coating, such as PET, PP or metallic film, such film surface is generally all through perfluoro-compound coating treatment
Or silicone coating processing；
Support layer material for patch of the present invention primarily serves the effect of attachment colloidal dispersion, has no specific limitation,
As long as skin sense is comfortable when being capable of providing the bonding force of enough colloids and supporting layer and sticking.Therefore, this product should have
Certain flexibility, that is, support layer material can follow the bending of skin and be moved to certain degree, and when it is bonded
It is apparent uncomfortable to that will not cause when skin surface.Can be the supporter of single layer structure, such as：Polyethylene, the modelings such as polyurethane
Expect film and metallic film, can also be laminate structures, in the supporter film upper layer of single layer structure and one or more its
Layer and film obtained from its material.
The preparation method of transdermal patch containing rotigotine as described above prepares the composition, uses coating machine
So that the composition is covered on protective film or release film, be dried in baking oven, organic solvent is made to volatilize, is covered with supporting layer and covers
Film is finally sliced and is packed.
Specifically, rotigotine and antioxidant (such as DL- alpha-tocopherols) are dissolved, in the high score based on polyisobutene class
It in sub- polymer, is coated with coating machine after mixing, so that drug containing colloid is uniformly covered on protective film or release film, then
It is dried in baking oven, organic solvent is vapored away, then supporting layer overlay film is finally sliced and is wrapped with mold with roller
Dress.
Beneficial effects of the present invention are：
Transdermal patch containing rotigotine prepared by the present invention, uses Medical PSA, C-H skeletons compared with
Long and straight, only end group has unsaturated bond, and since double bond is few, response location is few, colloidal dispersion itself have it is highly stable, it is weather-proof
Property, heat resistance and ageing resistance are good and at low cost, and material is easy to get, and operability is strong.Except polyisobutene framework material itself
Outside, the property that other materials adjust patch can also be added, such as viscous force conditioning agent, in addition to this polybutene material passes through addition
Some additives, moreover it is possible to achieve the effect that unexpected, such as colloid softening agent, initial purpose is to reduce the viscosity of pressure sensitive adhesive, just
In multicomponent dispersion, its wetting property is processed and improved, initial adhesion force and hand feel performance are improved, however, testing favorite outgoing
Existing, softening agent is usually liquid preparation at room temperature, has certain mobility, can reduce the phase between drug and patch substrate
Interaction significantly improves mobility of the drug in patch substrate, and then improves the transdermal release performance of drug.In conclusion
The present invention is the transdermal patch of the rotigotine prepared on this basis under the premise of meeting some conventional characters of patch, is also had
Have the characteristics that drug release property and percutaneous permeability from patch are excellent.
Description of the drawings
Fig. 1 is the structural schematic diagram of a preferred embodiment of the present invention.
Fig. 2 is composition 1-1, composition 1-2 patches unit area Percutaneous permeability-time plot.
Fig. 3 is 11 patch of composition and 1 patch unit area Percutaneous permeability of reference examples-time plot.
Fig. 4 is 12 patch of composition and 1 patch unit area Percutaneous permeability of reference examples-time plot.
Fig. 5 is 13 patch of composition and 1 patch unit area Percutaneous permeability of reference examples-time plot.
Fig. 6 is 1 patch of composition and reference examples 1, reference examples 2 and reference examples 3 patch unit area Percutaneous permeability-time
Curve graph.
Fig. 7 is composition 1,5 patch of composition and reference examples 1 patch unit area Percutaneous permeability-time plot.
Fig. 8 is composition 1, composition 2,3 patch of composition and reference examples 1 patch unit area Percutaneous permeability-time
Curve graph.
Fig. 9 is the stability experiment result figure of composition 1.
Figure 10 is the stability experiment result figure of reference examples 2.
Figure 11 is the stability experiment result figure of blank control.
Specific implementation mode
The present invention is a large amount of the study found that by using polyphosphazene polymer isobutene, molecular weight ranges are by inventor
450000~2,100,000 and low molecular polyisobutylene, low molecular polyisobutylene molecular weight ranges are 1000~450,000 and viscous force is adjusted
Agent, dosage are less than 50%, Medical PSA prepared by preferably 5~40% (w/w), by rotigotine drug dissolution/dispersion
Wherein, it is prepared into the patch containing rotigotine, there is preferable permeability, wherein viscous force conditioning agent can be selected from：Polybutene,
The substance of low molecular polyisobutylene, acroleic acid binding agent, acetic acid/vinyl acetate co-polymer (EVA) and other adjustable viscous forces,
Wherein preferred polybutene, low molecular weight polycaprolactone butylene, more preferable low molecular weight polycaprolactone butylene.Wherein by adjusting viscous force conditioning agent in colloid
In ratio, help to improve passability of the rotigotine in colloid.
In addition, the viscous force conditioning agent described in polyisobutene Type of Collective objects system can also help to adjust added with other
The substance of viscous force, such as the other additives of tackifier, plasticizer, thermoplastic resin, thermoplastic resin refer to common adjust and just glue
One substance of power：Its softening point is 50~250 DEG C, and preferably 50~150 DEG C, include natural resin such as rosin and its derivative
Object, terpene resin, terpene phenol resin etc., synthesis resinoid includes Petropols, xylene resin etc..Its use ratio is described
The weight ratio of polyisobutene Type of Collective object should be less than 50%, and the ratio of preferably 5~40% (W/W) is added to synthesis colloid composition
In.
The composition of the present invention adds colloid softening agent in preparation process, such as atoleine, light liquid paraffin, low
Molec weight polyisobutylene, lanolin, lubricant grease etc., preferred liquid paraffin, light liquid paraffin, more preferable light liquids stone
Wax.The stability of patch can be improved in the addition of colloid softening agent, avoids active constituents of medicine from the precipitation in preparation.Except this
Except, the addition of colloid softening agent can improve mobility of the drug in matrix, and drug is made to be easier to be detached from from matrix, from
And the effect of increasing the percutaneous abilities of drug, enhancing drug.In addition to this, the present invention also has multiple advantage, due to this prescription
Material used exists from structure from commercial product certain different, avoids that commercial product is that may be present unstable to ask
Inscribe
It is also added into the ingredients such as other fillers such as starch, superfine silica gel powder.These ingredients can be carried by its hydrophilicity
High patch is pasting wettability when using, and improves viscous force state and comfort when sticking.
Illustrate the content of present invention with reference to specific embodiment, but should not be construed as limiting the invention.Not
In the case of spirit of that invention and essence, to modifications or substitutions made by the method for the present invention, step or condition, this is belonged to
The range of invention.
Unless otherwise specified, the conventional means that technological means used in embodiment is well known to those skilled in the art,
Agents useful for same is not specified to be all made of conventional commercial reagent.
Embodiment 1 is used to prepare the preparation of the transdermal patch composition containing rotigotine
Suitable glass container is taken, the rotigotine of recipe quantity, DL- in table 1 are added into suitable ethanol solution
Alpha-tocopherol, stirring to mixture are completely dissolved.Polyisobutene B100, B10 of recipe quantity in table 1, low molecular weight polycaprolactone butylene is taken to stir
Mix it is uniformly mixed, formed Medical PSA, in above-mentioned pressure sensitive adhesive be added colloidal silicon dioxide, light liquid paraffin, stir
It mixes and mixes to uniform；Drug solution is added thereto again, it is stirring while adding, until obtaining dispersed system, vacuum outgas system
It is standby to obtain composition 1-1 and 1-2.
Using use for laboratory small size coating machine (Britain, Elcometer), by obtained composition 1-1 and 1-2 release
It is coated on film, specific coating thickness should ensure that the content of dispersion of the unit area in drying bak stay is certain, i.e., per 10cm2Patch
Piece includes rotigotine 4.5mg.At one layer of thin uniform layer, 80 DEG C dry 30 minutes, are covered with supporting layer.It is as shown in Figure 1 this
Invention patch configurations schematic diagram, wherein 1 is supporting layer, 2 be the self-adhesive matrix layer containing active constituent rotigotine.
The comparative test of 1. patch substrate of table
The rotigotine burst size in above-mentioned each composition percutaneous plaster is detected, using the FRANZ transdermal diffusion apparatus of improvement
(U.S., logan, ACS-100 types transdermal diffusion apparatus)；Experimental vehicle is using the corpse skin of purchase (using the human milk in postoperative 2 hours
Room skin is after removing subcutaneous layer of fat, and -30 DEG C of refrigerations are spare after physiological saline is cleaned)；The transdermal practical face of patch in experiment
Product is 1.98cm2, 32 DEG C, mixing speed 500rpm, reception tank volume 14ml of bath temperature, reception medium is using pH6.8 phosphoric acid
Salt buffer.Patch is pasted on keratoderma, is fixed on reception tank, timing sampling 4.5ml supplements 32 DEG C of constant temperature immediately
Blank receiving liquid.Sample is analyzed using high performance liquid chromatography (Shimadzu LC-20A types), is calculated according to the size of transit dose
The unit area of drug adds up transit dose, sample size：Each embodiment or the test article of reference examples patch select 2~6 samples；
Since the transdermal data of sample are influenced by skin-derived and state, experiment every time selects same position same next
The skin in source carries out experiment investigation.Experimental method refers to《Percutaneous dosing novel form》(Zheng Junmin, People's Health Publisher, 2006
Year December publishes page 265) experimental method introduced carries out percutaneous penetration.
Testing result is shown in Table 2.Composition 1-1, composition 1-2 patches unit area Percutaneous permeability-time plot are shown in
As shown in Figure 2.
Table 2
According to previous experiences, increases ratio of the low molecular weight polyisobutene ingredient in prescription, API can be improved in glue
Transmission property in body.The present invention improves the proportion of low molecular weight polyisobutene in polyisobutene, in-vitro percutaneous to its
Release behavior is investigated.As a result, it has been found that increasing the ratio of low molecular weight polyisobutene, inhibition is played in patch instead
The effect of drug release.
The comparative test of the different softening agents of embodiment 2
Type screening to softening agent, to by changing softening agent, improve its penetrating behavior, the softening different to three kinds
Agent：Light liquid paraffin, atoleine, glycerine are investigated, and component and dosage used are shown in Table 3, and preparation method uses embodiment 1
Described in method.
Component and dosage used in table 3.
Wherein, above-mentioned Medical PSA be use parts by weight for 30.7 polyisobutene (Polyisobutylene
(oppanol B100, viscosity average molecular weigh 1,000,000)), the polyisobutene (Polyisobutylene that parts by weight are 30.7
(oppanol B10, viscosity average molecular weigh 30,000)) and parts by weight be 5 low molecular weight polycaprolactone butylene (HV-300, viscosity average molecular weigh
1,260) it is uniformly mixed, forms Medical PSA, the Medical PSA in following embodiment is the side's of clicking here system
It is standby.
To the composition 11,12,13 of above-mentioned preparation, percutaneous plaster is prepared, is detected in above-mentioned each composition percutaneous plaster
The burst size of rotigotine, method is as described in example 1 above, while using commercially available rotigotine patch product
(content of UCB, rotigotine are 0.45mg/cm to NEUPRO2) reference examples 1 the most are detected.
To testing result, f2 factor pair ratios are carried out, wherein
The calculation formula of f2：
Wherein Rt and Tt respectively represents reference and the per unit Percutaneous permeability by test preparation t time points, and n is
Number of test points, the f2 factors are bigger, show that the similitude of two curves is higher, it is considered that, when the f2 factors are more than 50, the two tool
There is consistency.
Composition 11, composition 12,13 testing result of composition and the ratio for carrying out the f2 factors prepared by different softening agents
Compared with the results are shown in Table 4, table 5, table 6.
Table 4
Table 5
Table 6
In table 4,5,6 comparative example 1 results showed that the skin of each selection because its position difference, lead to the transmission of drug
Rate is also different, and unit area Percutaneous permeability-time plot is drawn according to the data in table, specific such as Fig. 3, figure
4, shown in Fig. 5, the results showed that the best results of light liquid paraffin.
Embodiment 3 is used to prepare the preparation of the transdermal patch composition containing rotigotine
Composition 1：
Suitable glass container is taken, the rotigotine, anti-bad of recipe quantity in table 7 is added into suitable ethanol solution
Hematic acid palmitate is completely dissolved with totally disappeared rotation-a- tocopherols, stirring to mixture.
The Polyisobutylene pressure sensitive adhesive of recipe quantity in table 1 is taken, atoleine is added, is stirred to uniform；Again by medicine
Object solution is added thereto, stirring while adding, until obtaining dispersed system, vacuum outgas.Use the small-sized coating of use for laboratory
Machine (Britain, Elcometer), obtained colloidal dispersion is coated on release film, specific coating thickness should ensure that drying
The content of dispersion of unit area in bak stay is certain, i.e., per 10cm2Patch includes rotigotine 4.5mg.It is uniform thin at one layer
Layer, 80 DEG C dry 30 minutes, are covered with supporting layer.
Composition 2：
The difference is that, each substance is added by table 7 with composition 1, added with silicone pressure-sensitive adhesive, liquid stone is not added
Wax.
Composition 3：
The difference is that, each substance is added by table 7 with composition 1, added with the quick glue of acrylic compounds, liquid stone is not added
Wax.
Composition 4：
The difference is that, each substance is added by table 7 with composition 1, atoleine and superfine silica gel powder is added, stirring is mixed
It is bonded to uniformly, then drug solution is added thereto.
Composition 5：
The difference is that, add each substance with composition 1 by table 7, atoleine and starch be added, be stirred to
Uniformly, then by drug solution it is added thereto.
Composition 6：
With composition 1 the difference is that, each substance is added by table 7, lanolin and superfine silica gel powder is added, is stirred
It is added thereto to uniform, then by drug solution.
Composition 7：
With composition 1 the difference is that, each substance is added by table 7, is first added into suitable ethanol solution
The polyvinylpyrrolidone of recipe quantity, ascorbyl palmitate and rotation-a- tocopherols, rotigotine are totally disappeared in table 1, stirred
It is completely dissolved to mixture.
Composition 8：
The difference is that, each substance is added by table 7 with composition 1.
Reference examples 1
For commercially available rotigotine patch product NEUPRO, (content of UCB, rotigotine are 0.45mg/
cm2)。
Reference examples 2-3
According to the method for composition 1, according to each component in the drug-reservoir layer provided in table 7 and its content (parts by weight),
Prepare the patch of reference examples 2, reference examples 3.Softening agent atoleine is free of wherein in reference examples 2；Compared to control in reference examples 3
Example 2 is used only polyacrylic pressure sensitive adhesive and substitutes Medical PSA.
The dosage of each component in 7. each embodiment of table
Note：All embodiments and reference examples (laboratory sample for including the NEUPRO of reference examples 1) contain same amount of sieve
For Gao Ting (0.45mg/cm2), to ensure the comparativity of experimental result.
Percutaneous penetration is carried out using the experimental method that embodiment 1 is introduced to the composition of above-mentioned preparation.Composition 1 is made
Standby patch is shown in Table 8, Fig. 6 with reference examples 1, the experimental result of reference examples 2 and 3 patch of reference examples through people's Skin permeation rate in vitro
The patch and reference examples 1, reference examples 2 and 3 patch of reference examples prepared for composition 1 is bent through people's Skin permeation rate in vitro-time
Line chart (n=2), according to data in figure it can be found that the Ligustrazine hydrochloride amount of composition 1 is far above patch prepared by other systems
Piece (reference examples 3), and compared to the prescription (reference examples 2) without containing softening agent, composition 1 also shows apparent transdermal
Advantage also has apparent advantage compared with presently commercially available silicone system prescription.
F2 factor pair ratios are carried out to transdermal curve and the results are shown in Table 8.
Table 8
Due to the patch that reference examples 1 are prepared using silicone pressure-sensitive adhesive expensive currently on the market, and simple use
Patch (reference examples 2, reference examples 3) transdermal value prepared by other pressure sensitive adhesives is too low, cannot reach requirement completely, the application carries
To composition 1 be improved on the basis of reference examples 2, by the way that other materials are added, and reached identical with reference examples 1
Transdermal test in vitro releasing effect can carry out further clinical research, reach corresponding therapeutic effect.
Patch and 1 patch of reference examples prepared by composition 1, composition 4 is through people's Skin permeation rate in vitro-time graph
(n=2) is schemed as shown in fig. 7, on the basis of composition 1, increases and is partially filled with object, such as superfine silica gel powder, further improves patch
The viscous force state of piece.The transdermal situation of composition 4 and composition 1 is investigated and is found, after the filler of part is added, can adjusted
On the basis of patch viscous force state, its transdermal is not impacted.
The in-vitro percutaneous penetrating situation of composition 1,2,3 and reference examples 1, the results are shown in Table 9, the results showed that, composition 1,2,3
With the in-vitro percutaneous penetrating situation no difference of science of statistics of reference examples 1, therefore, colloidal dispersion is not limited only to polyisobutene matrix,
Include polyisobutene and silicone, the mixture system of acrylic substrate.
Table 9
All f2 factors are compared with reference examples 1, as a result see Fig. 8, the results showed that, present composition 1-3's
Transdermal result will be substantially better than the transdermal result of reference examples 1.It since reference examples 1 are commercial samples, is widely used, has in clinic
There is good therapeutic effect, and the composition 1-3 prepared has good transdermal permeation characteristics, is fully able to meet in clinical treatment
It is required that.
4 stability experiment of embodiment
By composition 1, reference examples 2, blank control, (blank control selected in the present embodiment is release film, uses microscope
Whether have impurity on observation release film, avoid interfering experiment, the material of release film of the invention is PET) it is placed on 40
It ± 2 DEG C, under conditions of humidity 75 ± 5%, places 2 months, carries out crystallization situation and investigate.In pharmacy, often by such phenomenon
Referred to as aging phenomenon.Wherein, drug is converted from amorphous state for stable drug crystallization, and degree of scatter is reduced, this turn
Changing reduces the thermodynamic activity of drug.And the decline of drug thermodynamic activity is possible to that the reduction of drug dissolution can be caused,
The decline of drug transdermal performance, to reduce its therapeutic effect.Using micro- sem observation, it crystallizes situation, microscope for this experiment
(microscope model BX51, Japanese Olympus) is directly observed, microscope magnification 10 × 10, and is taken pictures, as a result such as
Shown in Fig. 9,10,11, wherein Fig. 1 is product prepared by composition 1, the results showed that no crystal is precipitated, and sample is more stable, Fig. 2
The product prepared for reference examples 2, the results showed that have crystal precipitation, wherein top is crystallization, and lower section is common sample, is illustrated pair
2 samples are unstable as usual；Fig. 3 blank control examples observe release film surface since the observation of sample is using PET as release film
It avoids in experimentation, the interference that the impurity on release film may be brought.
Claims (12)
1. a kind of composition being used to prepare the transdermal patch containing rotigotine, which is characterized in that it includes a effective amount of sieve
For Gao Ting and self-adhesive matrix, the self-adhesive matrix includes Medical PSA and colloid softening agent.
2. composition according to claim 1, which is characterized in that the Medical PSA includes being by weight proportion
1:10~10:The low molecular weight polycaprolactone that the polyphosphazene polymer isobutene and molecular weight that 1 molecular weight is 450,000~2,100,000 are 1000~450,000
Isobutene and viscous force conditioning agent, the colloid softening agent are atoleine, light liquid paraffin, low molecular weight polyisobutene, sheep
Hair fat, lubricant grease, preferred liquid paraffin, light liquid paraffin, more preferable light liquid paraffin, the viscous force conditioning agent choosing
From：Polybutene, low molecular weight polycaprolactone butylene, acroleic acid binding agent or acetic acid/vinyl acetate co-polymer, wherein it is preferred that polybutene, low
The molecular weight of molecule polybutene, more preferable low molecular weight polycaprolactone butylene, the low molecular weight polycaprolactone butylene is 500~1500, the viscous force tune
The dosage for saving agent is that the weight ratio of the Medical PSA is less than 55%, preferably 5~44%.
3. composition according to claim 1, which is characterized in that the Medical PSA is in the self-adhesive matrix
Weight ratio be 20%~99%, preferably 40%~77%；The colloid softening agent is in the weight ratio of the self-adhesive matrix
Less than 55%, preferably smaller than 44%, it is further preferably no larger than 33%, more preferable 1~22%；The rotigotine is in the combination
Weight ratio in object is 5%~20%, preferably 8%~15%.
4. composition according to claim 1, which is characterized in that the self-adhesive matrix further include have silicone pressure-sensitive adhesive or
Acrylic pressure-sensitive adhesivee, the mass percentage of the silicone pressure-sensitive adhesive or acrylic pressure-sensitive adhesivee in the self-adhesive matrix are
0~22%, preferably 0~16.5%.
5. composition according to claim 1, which is characterized in that the self-adhesive matrix further includes penetration enhancer, institute
It is 0%~15%, preferably 0.5%~7% that penetration enhancer, which is stated, in the weight ratio of the self-adhesive matrix, the penetration enhancer
For Laurocapram, Azone, oleic acid or lauric acid.
6. composition according to claim 1, which is characterized in that the self-adhesive matrix further includes surfactant-based object
Matter, the surfactant substance are tween, sapn, sldium lauryl sulfate；Alcohols and polyalcohols, amine and amides.
7. composition according to claim 1, which is characterized in that the self-adhesive matrix further includes solvent misture, described
Tackifying resin be rosin derivative, cyclopentadiene or isoprene, the self-adhesive matrix weight ratio be 5%~
25%.
8. composition according to claim 1, which is characterized in that the self-adhesive matrix further includes stabilizer, described steady
It is 0%~15%, preferably 0.5%~7% to determine agent in the weight ratio of the self-adhesive matrix, and the stabilizer is polyvinyl pyrrole
Alkanone class, poloxamer, polyethylene glycol.
9. composition according to claim 1, which is characterized in that the self-adhesive matrix further includes having other fillers,
Other fillers are 0%-15%, preferably 0.5%-7%, other fillers in the weight ratio of the self-adhesive matrix
For starch, silica, colloidal silicon dioxide or superfine silica gel powder.
10. composition according to claim 1, which is characterized in that the self-adhesive matrix layer further includes antioxidant, institute
State antioxidant be ascorbyl palmitate, sodium pyrosulfite, DL- alpha-tocopherols or one kind in dibutyl hydroxy toluene or
Several mixtures, the dosage of the polyphenoils are the 0.01%~2% of the self-adhesive matrix layer.
11. a kind of transdermal patch containing the composition as described in claim 1-10 is any.
12. the preparation method of transdermal patch described in claim 11, which is characterized in that prepare the composition, use coating machine
So that the composition is covered on protective film or release film, be dried in baking oven, organic solvent is made to volatilize, is covered with supporting layer and covers
Film is finally sliced and is packed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710588689.8A CN108451934B (en) | 2017-07-19 | 2017-07-19 | Transdermal patch containing rotigotine and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710588689.8A CN108451934B (en) | 2017-07-19 | 2017-07-19 | Transdermal patch containing rotigotine and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108451934A true CN108451934A (en) | 2018-08-28 |
| CN108451934B CN108451934B (en) | 2020-11-10 |
Family
ID=63220246
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710588689.8A Active CN108451934B (en) | 2017-07-19 | 2017-07-19 | Transdermal patch containing rotigotine and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108451934B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109908112A (en) * | 2019-04-19 | 2019-06-21 | 内蒙古科尔沁药业有限公司 | A kind of rubber paste emplastrum of not allergy and preparation method thereof |
| CN112300710A (en) * | 2020-10-28 | 2021-02-02 | 江苏集萃新型药物制剂技术研究所有限公司 | Drug-loaded pressure-sensitive adhesive composition, drug-loaded pressure-sensitive adhesive material and transdermal patch |
| WO2023110570A1 (en) * | 2021-12-14 | 2023-06-22 | Basf Se | Stabilisation of polyisobutene |
| WO2024040860A1 (en) * | 2022-08-24 | 2024-02-29 | 新领医药技术(深圳)有限公司 | Rotigotine transdermal drug delivery system inhibiting crystallization, method for preparing same, and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101628431A (en) * | 2008-07-16 | 2010-01-20 | 日东电工株式会社 | Process for producing adhesive patch |
| WO2012084969A1 (en) * | 2010-12-22 | 2012-06-28 | Hexal Ag | Adhesive composition containing rotigotine and transdermal therapeutic system comprising the adhesive composition |
| CN106604748A (en) * | 2014-05-21 | 2017-04-26 | Sk化学株式会社 | Rotigotine-containing transdermal absorption preparation with improved stability |
-
2017
- 2017-07-19 CN CN201710588689.8A patent/CN108451934B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101628431A (en) * | 2008-07-16 | 2010-01-20 | 日东电工株式会社 | Process for producing adhesive patch |
| WO2012084969A1 (en) * | 2010-12-22 | 2012-06-28 | Hexal Ag | Adhesive composition containing rotigotine and transdermal therapeutic system comprising the adhesive composition |
| CN106604748A (en) * | 2014-05-21 | 2017-04-26 | Sk化学株式会社 | Rotigotine-containing transdermal absorption preparation with improved stability |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109908112A (en) * | 2019-04-19 | 2019-06-21 | 内蒙古科尔沁药业有限公司 | A kind of rubber paste emplastrum of not allergy and preparation method thereof |
| CN109908112B (en) * | 2019-04-19 | 2022-04-19 | 内蒙古科尔沁药业有限公司 | Non-allergic rubber plaster and preparation method thereof |
| CN112300710A (en) * | 2020-10-28 | 2021-02-02 | 江苏集萃新型药物制剂技术研究所有限公司 | Drug-loaded pressure-sensitive adhesive composition, drug-loaded pressure-sensitive adhesive material and transdermal patch |
| WO2023110570A1 (en) * | 2021-12-14 | 2023-06-22 | Basf Se | Stabilisation of polyisobutene |
| WO2024040860A1 (en) * | 2022-08-24 | 2024-02-29 | 新领医药技术(深圳)有限公司 | Rotigotine transdermal drug delivery system inhibiting crystallization, method for preparing same, and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108451934B (en) | 2020-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10350174B2 (en) | Polyvinylpyrrolidone for the stabilization of a solid dispersion of the non-crystalline form of rotigotine | |
| AU2004253593B2 (en) | Transdermal hormone delivery system: compositions and methods | |
| TW537899B (en) | Composition for the transdermal administration of steroid drugs | |
| CN108451934A (en) | A kind of transdermal patch and preparation method thereof containing rotigotine | |
| DE10234673B4 (en) | Hot-melt TTS for the administration of rotigotine and process for its preparation, and use of rotigotine in the manufacture of a hot-melt TTS | |
| AU735944B2 (en) | Transdermal device for the delivery of testosterone | |
| WO1988001170A1 (en) | Steroidal drug-containing preparation for external use | |
| JP2011231125A (en) | Improved transdermal contraceptive delivery system and method | |
| US20050287195A1 (en) | Transdermal drug delivery systems | |
| Czech et al. | Acrylic pressure‐sensitive adhesive for transdermal drug delivery systems | |
| JPH0780758B2 (en) | Adhesive matrix for transdermal administration of active ingredient and process for its preparation | |
| KR19980701233A (en) | Composition and methods for transdermal delivery of acid-labile drugs | |
| TW201223528A (en) | Transdermal absorption preparation | |
| JPH09169635A (en) | Percutaneous absorption preparation | |
| WO2024037545A1 (en) | Dexmedetomidine transdermal composition, transdermal patch, and method for preparing transdermal patch and use thereof | |
| CN108606963B (en) | Compound contraceptive patch containing drospirenone and estrogen, preparation method and application | |
| Pethani et al. | Formulation Designing Factors For Development Of Repaglinide Transdermal Therapeutic System | |
| JPH04342531A (en) | Percutaneous drug | |
| JPH02235808A (en) | Patch for external use | |
| JPH064533B2 (en) | External pharmaceutical material | |
| JPH04360828A (en) | Percutaneously absorbable pharmaceutical preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |