CN107441066A - A kind of percutaneous absorption patch and its preparation method and application - Google Patents
A kind of percutaneous absorption patch and its preparation method and application Download PDFInfo
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- CN107441066A CN107441066A CN201710675659.0A CN201710675659A CN107441066A CN 107441066 A CN107441066 A CN 107441066A CN 201710675659 A CN201710675659 A CN 201710675659A CN 107441066 A CN107441066 A CN 107441066A
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
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- 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
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- 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
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Abstract
The invention discloses a kind of percutaneous absorption patch, includes back sheet, drug storing layer and protective layer；Wherein, drug storing layer includes adhesive composition, plasticiser, penetrating agent, moisturizing plasticizer and active medicine.The present invention is combined using two or more multicomponent alcoholics compounds, with at least one newborn acid compounds, or the ternary that at least one C6 C18 fatty acid ester compounds are formed promotees to ooze system, clinical requirement drug transdermal speed can not only be better met, and it can match with the amino alkyl methacrylate copolymer transdermal matrix containing plasticiser, patch is set under room temperature and/or body temperature to there is enough bonding forces to meet clinical demand, it is not necessary in the laminated extra adhesion layer of chip surface.The transdermal drug delivery system preparation technology of the present invention is relatively easy, and transdermal release speed is high and can also maintain enough stability.
Description
Technical field
The present invention relates to art of pharmacy.The present invention relates to a kind of percutaneous absorption patch, more particularly to Entecavir are transdermal
Absorption patch and its preparation method and application.
Background technology
Chronic hepatitis B is a kind of serious disease as caused by hepatitis B viruses (HBV), and high incidence and height are dead in the world
One of disease of rate.Hepatitis type B virus (hepatitis B virus, HBV) infection at present is in worldwide prevalence, but differently
The epidemic strength of area's HBV infection is widely different.Calculate that China is existing according to national Hepatitis B With Its Epidemics investigation result in 2006
Patient is about by the people of some Patients with Chronic HBV Infection about 93,000,000, wherein chronic hepatitis B (chronic hepatitis B, CHB)
20000000.The medicine of chronic hepatitis B patient antiviral therapy includes two major classes:Interferons and nucleosides (acid) class are disease-resistant
Cytotoxic drug.Nucleosides (acid) class antiviral drugs is to treat the Main Means of chronic hepatitis B, and its principle is by blocking or persistently pressing down
The duplication of hepatitis B viruses (HBV) processed in vivo, so as to mitigate or terminate inflammation, necrosis and fibrosis lesion, prevent lesion to
Liver function decompensation, hepatic sclerosis, liver failure and liver cancer development.5 kinds of oral nucleosides (acid) classes in Discussion on Chinese Listed are disease-resistant at present
Cytotoxic drug:Entecavir (entecavir, ETV), tenofovir disoproxil (tenofovir, TDF), Sebivo
(telbivudine, LdT), Aldoforwe ester (adefovir, ADV), Lamivudine (lamivudine, LAM).
Entecavir, which is that the chronic hepatitis B patient of the current World Health Organization and various countries guide recommendation is antiviral, to be controlled
One of first-line drug for the treatment of.Entecavir, being capable of selective depression HBV as a kind of potent oral guanosine analog
Replicate, it can be melted into active triphosphate by phosphoric acid in the cell, and with HBV reverse transcriptase natural substrate triphosphoric acid deoxidations
Guanosine competition produces drug effect.Entecavir has the incidence of Resistance mutation compared with other nucleosides (acid) class medicines
It is low, the characteristics of antivirus action is most strong and moderate.U.S. FDA in 2005 and state food pharmaceuticals administration general bureau
(CFDA) Entecavir tablet (trade name is ratified in succession:Bo Luding, Bristol-Myers Squibb Co.) it is used for CHB treatments.
The chemical name of Entecavir be 2- amino -9- [(1S, 3R, 4S) -4- hydroxyl -3- methylol -2- methylenes amyl group] -
1,9- dihydro -6H- purine-6-ones, structural formula are as follows:
Molecular formula C12H15N5O3, molecular weight 277.3, a crystallization water is usually contained, its monohydrate molecular formula
C12H15N5O3H20, molecular weight 295.3.Entecavir (entecavir) bulk drug is white to off-white powder, slightly soluble
Yu Shui, its solubility are 2.4mg/mL.The solubility increase in acid or alkaline aqueous solution.
But need to be oral daily using entecavir on hepatitis B, and at least medication half a year, the course for the treatment of are longer；Simultaneously
Clinical requirement patient's empty stomach medication is absorbed to strengthen it, this just exacerbates the adverse reaction of Entecavir, such as Nausea and vomiting, abdomen
Bitterly, diarrhoea, abdominal discomfort and indigestion etc., cause patient compliance poor, therapeutic effect is bad.In addition, Entecavir is discontinued
After rebound phenomenon occurs, cause palindromia, or even hepatic failure occurs, prognosis is bad.Further, current Oral administration is also
There is blood drug concentration the problem of obvious fluctuation occurs by curve over time.That is, when medicine in blood
Concentration it is too low when, it is difficult to give full play to curative effect；And poison can be produced due to overdose during the excessive concentration of medicine in blood
Property, body is increased burden.Meanwhile also there are intestines and stomach to the enzymolysis of medicine and liver first-pass effect etc. in oral administering mode
Problem, so that drug effect reduces.If it can extend Entecavir to patient's administration by way of cutaneous penetration to release
The medicine time, bioavilability is improved, reduces adverse drug reaction, reduces the stimulation of administration number of times and medicine to intestines and stomach, and then
Medication effect is improved, improves the compliance of patient, improves the quality of life of patient.
World patent WO2012048455A1 discloses antiviral drugs percutaneous absorption patch and preparation method thereof.Patent relates to
And to use amino alkyl methacrylate copolymer (EUDRAGIT E100) transdermal matrix and penetrating agent Laurocapram,
Eucalyptus oil prepares the specific embodiment of Entecavir percutaneous absorption patch.But disclosed is related to Entecavir Transdermal absorption patch
Not comprising any plasticiser in all embodiments of piece, this may result in amino alkyl methacrylate copolymer
The intrinsic viscosity of percutaneous absorption patch prepared by (EUDRAGIT E100) is insufficient, although being carried in disclosed embodiment
Go out and paster has been fixed on patient skin with facilitating in the laminated extra adhesion layer in Entecavir percutaneous absorption patch surface.But
Additional adhesion layer not only limit the percutaneous rate of antiviral drugs, and add patch processing and manufacturing difficulty and into
This.In addition, used by patent main penetrating agent Laurocapram (Azone) in terms of pharmacological activity and security there is also
Many disputes, there is presently no be approved by the FDA in the United States to use on pharmaceutical preparation.
The certain plasticizer of addition can form tool in amino alkyl methacrylate copolymer (EUDRAGIT E100)
It is known that sticking matrix, which is used for transdermal delivery device,.US patents 5993849, which disclose, a kind of to be used for skin and transdermal controls
The sticky transdermal matrix for the treatment of system, matrix include amino alkyl methacrylate copolymer (EUDRAGIT E100), plasticizing
Agent and Dicarboxylic Acids or tricarboxylic acid.Nicotine is applicable to, trinitin, hyoscine, clonidine, sweet smell is too
Buddhist nun, estradiol, testosterone, oxybutynin, Diclofenac, brufen, Ketoprofen, diltiazem, Propranolol, salbutamol, Ah
General azoles logical sequence, Ding Kana, atenolol, benzoporphyrin, buprenorphine, calcitonin, dithiol, benzophenone, multiple polypeptides, according to general
His shore, ethinylestradiol, methotrexate (MTX), naloxone and vitamin A and the cutaneous penetration of salicylic acid and its mixture.But the patent
Disclosed system do not have comprising any penetrating agent for mentioned medicine, and without disclosing any these medicines that are related to
Specific embodiment, involved medicine also do not include nucleosides (acid) class antiviral drugs.
Therefore, although the certain plasticising of addition in amino alkyl methacrylate copolymer (EUDRAGIT E100)
It is known that agent, which can form sticky transdermal matrix, but the penetrating agent for being further introduced into medicine and correlation on this basis is still faced with
All many challenges such as sticky deficiency and cold flow.Do not have yet with amino alkyl methacrylate copolymer at present
(EUDRAGIT E100) puts into clinical practice as the patch of transdermal matrix.
The deficiency exposed for existing program, the invention solves technical scheme include screening and methacrylic acid
The plasticiser pharmaceutically received and penetrating agent that aminoalkyl ester copolymer (EUDRAGIT E100) matches are combined for core
The transdermal matrix of glycosides (acid) class antiviral drugs, before improving embodiment it is existing viscosity deficiency and processing difficulties etc. ask
Topic, realizes the continual and steady cutaneous penetration of Entecavir.
It is surprising that in preferred embodiments, the present invention uses two or more multicomponent alcoholics compound groups
Conjunction, and at least one newborn acid compounds, or the ternary that at least one C6-C18 fatty acid ester compounds are formed promote to ooze system
Not only show and meet clinical requirement drug transdermal speed, and can be copolymerized with the amino alkyl methacrylate containing plasticiser
Thing transdermal matrix matches, and makes patch under room temperature and/or body temperature there is enough bonding forces to meet clinical demand.No
Need in the laminated extra adhesion layer of chip surface.The preferred embodiment of the invention has processing technology simplicity, equipment requirement
It is not high, suitable for industrialized production and product it is easy to use the advantages that.
The content of the invention
A kind of percutaneous absorption patch, the percutaneous absorption patch include：Back sheet, drug storing layer and protective layer.Wherein, medicine is store
Layer includes：
(A) adhesive composition；
(B) plasticiser；
(C) penetrating agent；
Described adhesive composition (A) is amino alkyl methacrylate copolymer, by butyl methacrylate, methyl
Dimethylamino ethyl acrylate and methyl methacrylate monomer by a certain percentage (1:2:1) by way of radical polymerization
Copolymerization forms.The copolymer of this definition under one's name, described copolymer include the EUDRAGIT under Evonik Roehm house flags
E100, or《Chinese Pharmacopoeia》The polyacrylic resin kind that version two in 2010 is recorded, entitled polyacrylic resin IV's
Acrylic resin product.The dalton (gram/mol) of EUDRAGIT E100 mean molecule quantities about 150,000, viscosity (20 DEG C) are
10cP, refractive index 1.38, density 0.815g/cm3, obtained alkali number are every gram of polymer 180mg KOH.The analog copolymer is long-term
Understood extensively by pharmaceutical industry with being used as the film coating of medicine or framework material.
Heretofore described amino alkyl methacrylate copolymer initial content is 10-90 parts by weight, is preferably
15-70 parts by weight, and more preferably 20-60 parts by weight.
The usual molecular weight having between 100 to 20,000 of material of plasticiser is suitable as, and is contained in the molecule
One or more hydrophilic radicals.Such as hydroxyl, ester group or amino.Heretofore described plasticiser (B) includes lemon dialkylaminobenzoic acid
Ester, acetyl tributyl citrate Arrcostab, triacetyl glycerine, alkyl phthalates, sebacic acid alkyl esters, sucrose ester, sorbierite
Ester, and Macrogol 4000 is to 20,000.Preferable plasticiser is triethyl citrate, ATEC, decanedioic acid
Dibutyl ester, triacetyl glycerine.Preferred plasticiser is triethyl citrate.
The addition of plasticiser can be according to the physical property feature and bag of amino alkyl methacrylate copolymer
Include the antiviral drugs certain drug formulation and penetrating agent requirement including Entecavir to be adjusted, to make patch in room temperature
And/or enough bonding forces are obtained under body temperature and the generation of cold flow will not be caused.Generally, plasticizer initial content should be with
Based on 30 parts by weight (preferably no more than 20 parts by weight).
Based on the amount of amino alkyl methacrylate copolymer used in the present invention, described plasticiser initial content is 1
To 30 parts by weight, preferably 3 to 25 parts by weight.More preferably 5 to 20 parts by weight.
Penetrating agent refers to that one kind well known in the art can overcome skin barrier effect, increase drug transdermal speed or increase medicine
The material of the transdermal quantity of thing.Penetrating agent (C) described in the present invention, is combined by two or more multicomponent alcoholics compounds, and extremely
A kind of few newborn acid compounds, or at least one fatty acid ester compound combine.
Described polyol compound includes 1,2-PD, 1,3-PD, 1,2- butanediol, 1,3-BDO, and 1,
The low-carbon multi alcoholic compound such as 4- butanediols, and polyethylene glycol 200,400,600, under the grade normal temperature of polypropylene glycol 200,400,600
For the polyhydric alcohol polymer of liquid.Preferable two or more multicomponent alcoholics compounds are combined as 1,2-PD, polyethylene glycol
400。
Described at least one newborn acid compounds include：Lactic acid, calcium lactate, sodium lactate, zinc lactate, ferrous lactate, breast
Acetoacetic ester, butyl lactate, the own ester of lactic acid, n-octyl lactate, lactic acid last of the ten Heavenly stems ester, lactic acid lauryl ester, lactic acid myristyl alcohol ester, lactic acid whale
Ceryl alcohol ester, menthyl lactate.Preferable polylactides are lactic acid, ethyl lactate.
Described at least one C6-C18 fatty acid ester compounds include：Isopropyl myristate (IPM), polyethylene glycol
Monolaurate (PEGML), PGML (PGML), Propylene glycol monodecanoate (PGMC), glyceryl monolaurate
(GML), glycerin mono-fatty acid ester (GMO), ethyl oleate.Preferred fat acid esters compound is PGML
(PGML), isopropyl myristate (IPM).More preferably fatty acid ester compound isopropyl myristate (IPM).
Other well known penetrating agent, such as C6-C18 fatty acid compounds such as capric acid, laurate, myristic acid and oil
Acid, C6-C18 aliphatic alcohols compound such as decyl alcohol, laruyl alcohol and oleyl alcohol and terpenoid ratio such as eucalyptus oil, lemon
Alkene, the equally applicable transdermal drug delivery system described in the invention of terpinol.
Polyalcohol serves mainly to facilitate antiviral drugs of the dissolving including Entecavir, also has to the medicine certain
Mechanism.Two kinds of multicomponent alcoholics compound collaborations use equally has solute effect more to the antiviral drugs including Entecavir
Good and dissolution system is more stable.By two kinds of multicomponent alcoholics compounds and at least one newborn acid compounds, or at least one fat
Fat acid esters compound, which merges, to be used, and the osmotic effect of the antiviral drugs including Entecavir is substantially increased.If
Penetrating agent only selects multicomponent alcoholics compound or newborn acid compounds, or one kind in fatty acid ester compound, then dissolving and
Osmosis will be obvious insufficient, can not produce a desired effect.More importantly preferred embodiment of the invention kind is used
Two kinds of multicomponent alcoholics compounds and at least one newborn acid compounds, or at least one fatty acid ester compound formed
Ternary promotees to ooze system and not only show to meet clinical requirement drug delivery rate, and can be with the methacrylic acid ammonia containing plasticiser
Base alkyl ester copolymer transdermal matrix matches so that patch is had enough bondings under room temperature and/or body temperature
Power and the generation that cold flow will not be caused.
Two kinds of multicomponent alcoholics compound compounds of the present invention, at least one newborn acid compounds, or it is at least one
C6-C18 fatty acid compounds, or the combination penetrating agent usage amount of at least one fatty acid ester compound is respectively：Low-carbon
Polyol compound is 1-40 parts by weight；Polyhydric alcohol polymer 1-20 parts by weight；At least one newborn acid compounds are 0.1-15
Parts by weight, or at least one C6-C18 fatty acid ester compounds are 0.1-15 parts by weight.It is preferred that low-carbon multi alcoholic compound is
5-20 parts by weight；Polyhydric alcohol polymer 3-15 parts by weight；At least one newborn acid compounds are 0.5-10 parts by weight, or at least one
Kind C6-C18 fatty acid compounds are 0.5-10 parts by weight, or at least one fatty acid ester compound is 0.5-10 weight
Part.
The percutaneous absorption patch of the present invention further comprises moisturizing plasticizer (D).Moisturizing plasticizer is to further improvement
The viscosity and cohesive strength of amino alkyl methacrylate copolymer transdermal matrix are adjusted, avoid transdermal matrix appearance from peeling off,
Comfortableness when phenomena such as cold flow, improving the stability of medicine in storage and during use, and wearing.Reduce or eliminate transdermal
Excitant of the device to skin.Moisturizing plasticizer be usually pharmacy industry as auxiliary material it is receptible and compatible with body series
Any one of hydrophilic high mol.Described moisturizing plasticizer refers at least one polyvinylpyrrolidone, or polyethylene pyrrole
Pyrrolidone/vinyl acetate copolymer, or ammonio methacrylate copolymer.
Described polyvinylpyrrolidone (PVP) refers to the polymer made of NVP monomer.Poly- second
The molecular weight of alkene pyrrolidone is excellent in the range of 2000 to 2500000 dalton (gram/mol) (being given as weight average molecular weight)
The molecular weight of the polyvinylpyrrolidone of choosing is in the range of the dalton (gram/mol) from 28000 to 1500000.More preferably
The molecular weight of polyvinylpyrrolidone is in the range of the dalton (gram/mol) from 1,000,000 to 1,500,000.It is various etc.
The PVP products of level are purchased from BASF AG (Ludwigshafen, Germany), or ISP companies (Wayne, New Jersey,
USA).The title of its commodity is respectively Kollidon series or Plasdone series.The PVP product lines point of Kollidon under one's name
Do not include：K-12PF (molecular weight=2,000-3,000)；K-17PF (molecular weight=7,000-11,000)；K-25 (molecular weight=
28,000-34,000)；K-30 (molecular weight=44,000-54,000)；With K-90 (molecular weight=1,000,000-1,500,
000).The PVP product lines of Plasdone under one's name include respectively：K-12 (molecular weight=4,000)；K-17 (molecular weight=10,
000)；K-25 (molecular weight=34,000)；K-29/32 (molecular weight=58,000)；With K-90 (molecular weight=1,300,000).
Preferable polyvinylpyrrolidone includes Kollidon K-30, K-90 and Plasdone K-29/32, and K-90.More preferably
Polyvinylpyrrolidone is Plasdone K-90.
Described polyvinylpyrrolidone//vinyl acetate copolymers refer to by polyvinylpyrrolidone monomer and acetic acid second
Polymer made of alkene alicyclic monomer.Wherein, polyvinylpyrrolidone weight accounts for 60%, and the weight of vinyl acetate resin accounts for 40%.Institute
The polyvinylpyrrolidone//vinyl acetate copolymers product stated is purchased from BASF AG (Ludwigshafen, Germany),
Or ISP companies (Wayne, New Jersey, USA).The title of its commodity is respectively Kollidon VA64 or Plasdone S-
630；.Kollidon VA64 molecular weight is 40,000；Plasdone S-630 molecular weight is in 24,000-30,000.
Described ammonio methacrylate copolymer refers to ethyl acrylate, methyl methacrylate and methyl-prop
Olefin(e) acid trimethyl ammonium chloride base acetate monomer by a certain percentage (1:2:0.1) (Eudragit RL 100) or (1:2:0.2)
The copolymer that (Eudragit RS 100) is copolymerized by way of radical polymerization.
Described ammonio methacrylate copolymer includes the product E udragit under Evonik Roehm exabytes
RL100, RLPO and RS100, RSPO.Can be with the presence of chlorion；The dalton (gram/mol) of mean molecule quantity 150000；Viscosity (20
DEG C) it is up to 15Cp, refractive index 1.380-1.385.Density 0.815-0.835g/cm3.Wherein, the sun of Eudragit RL 100 from
The ratio of sub- ester group and neutral alkyl is 1:20, obtained alkali number is every gram of polymer 28.lmg KOH；Eudragit RS 100
The ratio of cation ester group and neutral alkyl is 1:40, obtained alkali number is every gram of polymer 15.2mg KOH.Described quaternary amine
Methacrylate copolymer also includes《Chinese Pharmacopoeia》The polyacrylic resin kind that version two in 2010 is recorded, there is poly- first
Ammonium acrylate ester I, poly- first ammonium acrylate ester II acrylic resin product.Preferable product is Eudragit RL100 or poly- first
Ammonium acrylate ester II.
Heretofore described moisturizing plasticizer initial content is 0 to 20 parts by weight, preferably 0 to 10 parts by weight.More preferably 0
To 5 parts by weight.Preferable Medicated Permeation rate is then extremely difficult to beyond the scope and keeps obtaining enough bonding forces.
The percutaneous absorption patch of the present invention further comprises active medicine (E).
Described active medicine (E) is core former times class antiviral drugs or pharmaceutically acceptable salt such as Entecavir, A De
Good fortune Wei vinegar, Lamivudine or stavudine.Preferably Entecavir, Entecavir hydrate or pharmaceutically acceptable Entecavir
Salt.Described pharmaceutically acceptable entecavir salt includes：Maleic acid Entecavir.Active medicine is preferably Entecavir.
Preferable active medicine dosage is 0.01-10 parts by weight in parts by weight in the present invention.It is of the invention preferred living
Property medicine usage amount is 0.05-5 parts by weight in parts by weight.Most preferably active medicine usage amount of the invention is in parts by weight
0.1-3 parts by weight.Transdermal amount can not meet the treatment effective dose of the medicament if its usage amount is too low；If on the contrary, make
Dosage is too high, then due in active medicine Entecavir in the present invention system really with existing for over-saturation dissolved state,
Easily cause active medicine crystallization to separate out, and then have influence on the transdermal release speed of active medicine Entecavir.It is in addition, too high
Drugloading rate is from the point of view of economy and inappropriate.
Percutaneous absorption patch structure in the present invention is lamination layer structure, comprising：Back sheet, drug storing layer and protective layer.
It is not particularly limited in back sheet of the present invention, the general back sheet in patch field can be used.Such as:It is poly-
The woven cloth of the retractilities such as ethene, polypropylene or non-telescoping property, non-woven fabrics, polyethylene, polypropylene, polyethylene terephthalate
The membrane materials such as the polyester polymers such as ester, EVAc, vinyl chloride, aluminium film.Or the foaming such as urethane, polyurethane
Property membrane material.Above-mentioned membrane material can be used alone, and can also be formed using a variety of membrane materials are laminated.Such as polyethylene-aluminium-poly-
Ethene compound film material.And then in order to prevent electrostatic from being accumulated on carrier, can also form back sheet it is above-mentioned weave cotton cloth, nonwoven
Contain antistatic agent in the materials such as cloth, film.In addition, it is good anchoring properties with adhesive phase in order to obtain, can be by non-woven fabrics
Or woven cloth is mixed into gummy polymer layers, then combine to form back sheet with above-mentioned composite membrane.The thickness of back sheet, for film
For material, usually l0 μm -100 μm, preferably 15 μm -50 μm, for weaving cotton cloth, the porous piece such as non-woven fabrics, foaminess carrier
Material, usually 50 μm -2,000 μm, preferably 100 μm -1,000 μm.
Protective layer of the present invention refers to the general protection film layer in patch field.As protection film layer, can make
With the resin films such as the polyester such as glassine paper, polyethylene, polypropylene, polyethylene terephthalate, polystyrene, aluminium film, foaming
The film of the material such as polyethylene film or expanded polypropylene film or use the laminated film formed of two or more membrane materials in above-mentioned
Material.The present invention can also use the protection film layer that silicone surface processing has been carried out to above-mentioned membrane material, or carry out fluorine tree
Fat surface treatment protection film layer, implement embossed surface processing, plasma surface treatment, hydrophilic surface handle, it is hydrophobic
Property surface treatment etc. protection film layer etc..The preferred surface of protection film layer of transdermal patch of the present invention is carried out at silicone surface
The polyester film of reason.The thickness of protection film layer is usually 10 μm -200 μm, preferably 15 μm -150 μm.
Present invention also offers the preparation method of above-mentioned transdermal patch.Its preparation method comprises the following steps：First with rush
Low molecular polylol in penetration enhancer adds polyhydric alcohol polymer that active medicine solid dissolving is added into remaining penetrating agent solution,
Plasticiser, amino alkyl methacrylate copolymer, moisturizing plasticizer and cosolvent are mixed together, and are sufficiently stirred about 6
Hour, until it is solution complete miscibility, limpid, stand 15 minutes after the completion of stirring.Composition stands at least 3 hours to 12 hours,
Until being thoroughly degassed.Uniform colloid masking liquid will be obtained, using on coating process to protective layer material, described coating process bag
Include coating apparatus coating or hardened coating.Workable coating apparatus includes roll coater, die coating machine, intaglio plate roll coater, reverse roll
Painting machine, the roll coater that coincide, dipping roll coater, bar coater, knife, Bracewell coater etc..In addition, the drying of above-mentioned masking liquid is excellent
The heating-up temperature of choosing and carried out under drying time, under conditions of such as 40 DEG C -150 DEG C or so of temperature, 20-240 minutes or so
Carry out to get rid of cosolvent.It is laminated with back sheet again, it is punched, obtains the transdermal patch of three-decker.It is dried to contain grace
It is preferably lmg/cm2-100mg/cm2 for the gummy polymer layers weight per unit area of card Wei, more preferably 2mg/cm2-80mg/
cm2.Preferred l0 μm -600 μm of the thickness of the dried gummy polymer layers containing Entecavir, more preferably 30 μm of -300 μ
m.Gained transdermal patch can be put into the appropriate packaging for storage, such as paper bag and/or metallic foil bag, be saved in transdermal control
When treatment.
Present invention cosolvent used in preparation process refers to that one kind well known in the art can help active medicine grace to replace
The dissolving of card Wei, and with amino alkyl methacrylate copolymer, and the polyethylene pyrrole alkanone as moisturizing plasticizer, or
Polyvinylpyrrolidone//vinyl acetate copolymers, or ammonio methacrylate copolymer it is compatible low boiling it is organic
Solvent.Such as the mixture of acetone, ethyl acetate and absolute ethyl alcohol or these organic solvents.Heretofore described cosolvent is
Absolute alcohol.Initial content is 10-90 parts by weight, preferably 20-70 parts by weight, more preferably 30-60 weight in parts by weight
Part.
The present invention uses two or more multicomponent alcoholics compounds to combine, and at least one newborn acid compounds, or at least
The ternary that a kind of C6-C18 fatty acid ester compounds are formed promotees to ooze system, can not only better meet clinical requirement drug transdermal
Speed, and can match with the amino alkyl methacrylate copolymer transdermal matrix containing plasticiser, make patch in room
Under temperature and/or body temperature there is enough bonding forces to meet clinical demand, it is not necessary to laminated extra viscous in chip surface
Attached layer.Transdermal patch of the present invention has the advantages that processing technology is easy, equipment requirement is not high, easy to use.
Brief description of the drawings
Fig. 1 is the schematic cross-section of paster.Wherein, 1 be back sheet, 2 be drug storing layer (gummy polymer layers), 3 be protection
Layer (protection film layer).
Embodiment
The present invention is explained further below by embodiment, but embodiment to the present invention and is not limited in any way.
Fig. 1 represents the signal of transdermal drug delivery system (TCDS) paster for the Entecavir prepared and manufactured in embodiment 1
Property sectional view, it includes back sheet (1), drug storing layer (2), protective layer (3).
Embodiment 1
Entecavir 0.8g, propane diols 11.2g, polyethylene glycol 400 6.4g is taken to be put into together in triangular flask, bottle sealing,
In stirring 6 hours on magnetic stirring apparatus, until it is solution complete miscibility, limpid, stand 15 minutes after the completion of stirring.By lactic acid
2.8g, triethyl citrate 13.5g, amino alkyl methacrylate copolymer E100 40g, cosolvent absolute ethyl alcohol 72g mono-
Rise and be added in the triangular flask of solubilized solution decoction, bottle sealing, in being stirred 12 hours on magnetic stirring apparatus, stood after the completion of stirring
It is stand-by after 30 minutes.It will obtain what uniform colloid scraper coating machine or hardened coating were handled to silicone surface
On PET polyester film protective layer materials, 40 minutes are dried under the conditions of 80 DEG C to get rid of cosolvent, makes dried viscosity poly-
Entecavir content in compound layer is about 0.2/cm2.After cooling again with back sheet (SCOTCH PAK 1109,3M,
St.Paul, US) pressing, punching, 5cm X 5cm size is cut into, packs produce that drug storing layer thickness is 110 μm or so three
The transdermal patch of Rotating fields.
The Entecavir patch dermal penetration rate of 24 hours uses pig ear skin, is expanded by Valia-chien two-chamber osmotics
Dissipate pond and high performance liquid chromatography (HPLC) is evaluated.
Fresh pig ear, the outer Middle face of ear is taken to the position of have sharp ears, remove the skin of the cartilage and internal layer among ear,
Subcutaneous unnecessary fat to be cut, cuts flat whole, is then cut into diameter 20mm rounded nubs, subzero 21 DEG C of refrigerators save backup,
Using preceding immersion physiological saline 1h, can be used with filter paper suck dry moisture.
Between pig ear skin is close into two Room of VALIA-CHIEN osmotic cells, skin corium pastes towards receiving chamber, stratum corneum side
Upper Entecavir transdermal patch, the twoport of two Room is fixed with spring clip, 0.2mol/L phosphate-buffereds are added in receiving chamber
Liquid (PH 7.4) 3.4ml, the water temperature in osmotic cell interlayer is controlled at 32 ± 0.5 DEG C, electromagnetic agitation rotating speed 400r/min, by rule
800 μ l penetrating fluid is taken out after fixed 24 hours from receiving chamber, the transdermal of Entecavir in 24 hours penetrating fluids is determined with HPLC methods
Speed.As a result it is as shown in table 1.
Entecavir transdermal patch surface viscosity is investigated by 180 ° of peel strengths.Peel strength refers to appropriate pressure
The ability of pressure-sensitive adhesive product and the resistance interfacial separation showed between maxxaedium after power and time are pasted.
Before experiment, patch is removed into packaging material, placed more than 2 hours at room temperature without overlapping.By the patch back side
It is fixed on breadboard with double faced adhesive tape, is fixed test sample forward edge with sticking tape.By test sample adhesive layer with it is clean
Net polyester film bonding, then with pressure roller on test sample come rollback pressure, to ensure that abutting edge bubble-free is present.Test sample glues
After patch, tested after placing 20-40 minutes at room temperature.By 180 ° of polyester film free end doubling, film free end and
Left and right is held on testing machine breadboard respectively.Because making release surface be consistent with testing machine line.Testing machine with 300mm/min ±
10mm/min is continuously peeled off, and peels off the peel strength result that record testing machine is shown after terminating.For transdermal patch, peel off
Intensity should be in the range of 0.24-2.50kN/m.As a result it is as shown in table 1.
Comparative example 1
With reference to the embodiment 1 in world patent WO2012048455A1, amino alkyl methacrylate copolymerization is weighed
Thing EUDRAGIT E100 11.84g, are dissolved in advance with 17.76g ethyl acetate, and amino alkyl methacrylate copolymerization is made
Thing solution viscosity 29.6g (the solid thing charged material weight ratios of EUDRAIT E100 are 40%), adds antiviral drug of Entecavir
0.08g, transdermal enhancer Laurocapram 1.44g, eucalyptus oil 0.96g and propane diols 1.42g mixtures, and solvent ethyl acetate 16g
It is put into triangular flask bottle, bottle sealing, is stirred 15 hours on magnetic stirring apparatus together, then stands until bubble collapse.It will obtain
The PET polyester film protective layer materials that handle of uniform colloid scraper coating machine or hardened coating to silicone surface
On, 2 minutes are dried at being dried 2 minutes, 90 DEG C at then being dried 4 minutes, 60 DEG C at 40 DEG C to get rid of cosolvent, is cooled down
Pressed again with back sheet (SCOTCH PAK 1109,3M, St.Paul, US) afterwards, punching, it is 110 μ to pack and produce drug storage thickness degree
The transdermal patch of m or so three-decker.The transdermal speed of 24 hours of Entecavir transdermal patch is determined as described in Example 1
Rate and 180 ° of peel strengths.As a result it is as shown in table 1
Table 1：
| Embodiment 1 | Comparative example 1 | |
| 24h transdermal releases rate (μ g/cm2.h) | 14.08 | 1.13 |
| Peel strength (KN/m) | 0.75 | 0.01 |
The result of table 1 shows that the embodiment of the present invention 1 not only shows high drug transdermal speed, and peel strength can
To reach 0.75KN/m, this causes patch to obtain enough bonding forces under room temperature and/or body temperature.Review comparative example,
Peel strength only has 0.01KN/m.Sticky obvious deficiency.Need in the laminated extra adhesion layer in absorption adhesive patch surface or borrow it
Its servicing unit can be just fixed on skin.
Comparative example 2
Formula composition is substantially the same manner as Example 1, and penetrating agent only adds propane diols and combined with polyethylene glycol 400.By implementation
The method of example 1 is made patch and determines the percutaneous rate of Entecavir transdermal patch.As a result it is as shown in table 2.
Comparative example 3
Formula composition is substantially the same manner as Example 1, and penetrating agent only adds lactic acid.Patch is made simultaneously as described in Example 1
Determine the percutaneous rate of Entecavir transdermal patch.As a result it is as shown in table 2.
Table 2：
| Embodiment 1 | Comparative example 2 | Comparative example 3 | |
| 24h transdermal releases rate (μ g/cm2.h) | 14.08 | 3.22 | 12.31 |
The result of table 2 shows that the drug transdermal speed of embodiment 1 slightly above only adds the comparative example 3 of lactic acid penetrating agent, significantly
The comparative example 2 of penetrating agent is combined with polyethylene glycol 400 higher than addition propane diols.When this shows to use single penetrating agent respectively,
Because not having cooperative effect, its Entecavir mechanism can decrease.
Embodiment 2
Formula composition is substantially the same manner as Example 1, and triethyl citrate is substituted with dibutyl sebacate in embodiment 1.Press
The method of embodiment 1 is made patch and determines the percutaneous rate of 24 hours and 180 ° of peel strengths of Entecavir transdermal patch.
As a result it is as shown in table 3.
Embodiment 3
Formula composition is substantially the same manner as Example 1, and triethyl citrate is replaced with tributyl 2-acetylcitrate in embodiment 1
Generation.As described in Example 1 be made patch and determine Entecavir transdermal patch the percutaneous rate of 24 hours and 180 ° stripping
Intensity.As a result it is as shown in table 3.
Embodiment 4
Formula composition is substantially the same manner as Example 1, and triethyl citrate is substituted with triethylglycerides in embodiment 1.By reality
The method for applying example 1 is made patch and determines the percutaneous rate of 24 hours and 180 ° of peel strengths of Entecavir transdermal patch.Knot
Fruit is as shown in table 3.
Embodiment 5
Formula composition is substantially the same manner as Example 1, and triethyl citrate is replaced with ATEC in embodiment 1
Generation.As described in Example 1 be made patch and determine Entecavir transdermal patch the percutaneous rate of 24 hours and 180 ° stripping
Intensity.As a result it is as shown in table 3.
Table 3：
The result of table 3 is shown, preferable drug transdermal speed can be obtained using different types of plasticiser, and is peeled off strong
For degree in the range of 0.31-0.78KN/m, this causes above-mentioned patch to have enough bondings under room temperature and/or body temperature
Power.According to the result of table 3, the triethyl citrate in the preferable embodiment 1 of plasticiser.
Embodiment 6
Formula composition is substantially the same manner as Example 1, and penetrating agent lactic acid is substituted with ethyl lactate in embodiment 1.By embodiment 1
Method patch is made and determines the percutaneous rate of 24 hours and 180 ° of peel strengths of Entecavir transdermal patch.As a result such as table
Shown in 4.
Embodiment 7
Formula composition is substantially the same manner as Example 1, and penetrating agent lactic acid is replaced with isopropyl myristate (IPM) in embodiment 1
Generation.As described in Example 1 be made patch and determine Entecavir transdermal patch the percutaneous rate of 24 hours and 180 ° stripping
Intensity.As a result it is as shown in table 4.
Embodiment 8
Formula composition is substantially the same manner as Example 1, and penetrating agent lactic acid is with PGML (PGML) in embodiment 1
Substitute.As described in Example 1 be made patch and determine Entecavir transdermal patch the percutaneous rate of 24 hours and 180 ° stripping
From intensity.As a result it is as shown in table 4.
Embodiment 9
Formula composition is substantially the same manner as Example 1, and lactic acid is substituted with oleic acid in embodiment 1.It is made as described in Example 1
Patch and the percutaneous rate of 24 hours and 180 ° of peel strengths for determining Entecavir transdermal patch.As a result it is as shown in table 4.
Table 4：
The result of table 4 shows that ideal can be obtained by being combined using different types of penetrating agent with propane diols with polyethylene glycol 400
Drug transdermal speed, particularly propane diols, polyethylene glycol 400 and lactic acid and propane diols, polyethylene glycol 400 and lactic acid Pork and beans
Rush ooze effect of cool isopropyl propionate (IPM) the penetrating agent combination to medicine becomes apparent, and preferable penetrating agent can be used as to combine.Table 4
All embodiment peel strengths are located in the range of 0.51-0.75KN/m, and this illustrates above-mentioned patch under room temperature and/or body temperature
It is respectively provided with enough bonding forces.
Embodiment 10
Formula composition is substantially the same manner as Example 1, and 40g amino alkyl methacrylate copolymers E100 is changed to
48g.The patch measure Entecavir transdermal patch percutaneous rate of 24 hours is made as described in Example 1 and 180 ° are peeled off by force
Degree.As a result it is as shown in table 5.
Embodiment 11
Formula composition is substantially the same manner as Example 1, and the extra 1.6g polyvinylpyrrolidones that add are Plasdone K-90.
The patch measure Entecavir transdermal patch percutaneous rate of 24 hours and 180 ° of peel strengths are made as described in Example 1.Knot
Fruit is as shown in table 5.
Embodiment 12
Formula composition is substantially the same manner as Example 1, extra to add 1.6g ammonio methacrylate copolymers RL100.
The patch measure Entecavir transdermal patch percutaneous rate of 24 hours and 180 ° of peel strengths are made as described in Example 1.Knot
Fruit is as shown in table 5.
Embodiment 13
Formula composition is substantially the same manner as Example 1, and 40g amino alkyl methacrylate copolymers E100 is replaced by
36g polyacrylic resins IV.Patch is made as described in Example 1 and determines the Entecavir transdermal patch transdermal speed of 24 hours
Rate and 180 ° of peel strengths.As a result it is as shown in table 5.
Table 5：
The result of table 5 is shown, further adds amino alkyl methacrylate copolymer E100, and polyvinylpyrrolidone is
The drug transdermal speed and 180 ° of peel strengths that Plasdone K-90 are obtained are ideal.It is replaced by IV pairs of polyacrylic resin
180 ° of peel strengths have a great influence, but drug transdermal speed and 180 ° of peel strengths are in acceptable scope.These embodiments
It is very helpful to suppressing the generation of patch cold flow.
The transdermal drug delivery system preparation technology of the present invention is relatively easy, and transdermal release speed is high and can also maintain enough
Stability.
Claims (25)
1. a kind of percutaneous absorption patch, comprising：Protective layer, drug storing layer and back sheet；Wherein, drug storing layer includes：
(A) adhesive composition；
(B) plasticiser；
(C) penetrating agent；
Described adhesive composition (A) is amino alkyl methacrylate copolymer；Amino alkyl methacrylate is copolymerized
Thing is 10-90 parts by weight in parts by weight；
The plasticiser (B) has the molecular weight between 100 to 20,000, and contains one or more hydrophilic groups in the molecule
Group；The plasticiser is 1-30 parts by weight；
Described penetrating agent (C), is combined by two or more multicomponent alcoholics compounds, and at least one newborn acid compounds, or extremely
A kind of few fatty acid ester compound combines；Wherein, low-carbon multi alcoholic compound is 1-40 parts by weight；Polyhydric alcohol polymer
1-20 parts by weight；At least one newborn acid compounds are 0.1-15 parts by weight, or at least one C6-C18 fatty acid esters chemical combination
Thing is 0.1-15 parts by weight.
A kind of 2. percutaneous absorption patch according to claim 1, it is characterised in that：
Described amino alkyl methacrylate copolymer (A) is by butyl methacrylate, dimethylaminoethyl second
Ester and methyl methacrylate monomer are copolymerized by way of radical polymerization by a certain percentage to be formed；Described metering system
Sour aminoalkyl ester copolymer is 15-70 parts by weight；
The plasticiser includes hydroxyl, ester group or amino；It is sweet including citric acid alkyl esters, acetyl tributyl citrate Arrcostab, three acetic acid
Grease, alkyl phthalates, sebacic acid alkyl esters, sucrose ester, sorbitol ester, and Macrogol 4000 are to 20,000；Institute
It is 3 to 25 parts by weight to state plasticiser dosage.
In the penetrating agent, described polyol compound includes 1,2-PD, 1,3-PD, 1,2- butanediol, and 1,3-
The low-carbon multi alcoholic compound such as butanediol, BDO, and polyethylene glycol 200,400,600, polypropylene glycol 200,400,600
Deng the polyhydric alcohol polymer under normal temperature being liquid；
Described at least one newborn acid compounds include：Lactic acid, calcium lactate, sodium lactate, zinc lactate, ferrous lactate, lactic acid second
Ester, butyl lactate, the own ester of lactic acid, n-octyl lactate, lactic acid last of the ten Heavenly stems ester, lactic acid lauryl ester, lactic acid myristyl alcohol ester, lactic acid cetanol
Ester, menthyl lactate；
Described at least one C6-C18 fatty acid ester compounds include：Isopropyl myristate (IPM), the polyethyleneglycol moon
Cinnamic acid ester (PEGML), PGML (PGML), Propylene glycol monodecanoate (PGMC), glyceryl monolaurate
(GML), glycerin mono-fatty acid ester (GMO), ethyl oleate.Preferred fat acid esters compound is PGML
(PGML), isopropyl myristate (IPM)；Wherein, low-carbon multi alcoholic compound is 5-20 parts by weight；Polyhydric alcohol polymer is 3-
15 parts by weight；At least one newborn acid compounds are 0.5-10 parts by weight, or at least one C6-C18 fatty acid compounds are
0.5-10 parts by weight, or at least one fatty acid ester compound are 0.5-10 parts by weight.
A kind of 3. percutaneous absorption patch according to claim 2, it is characterised in that：
Described amino alkyl methacrylate copolymer (A) is by butyl methacrylate, dimethylaminoethyl second
Ester and methyl methacrylate monomer press 1:2:1 is copolymerized by way of radical polymerization and forms；Described copolymer includes
EUDRAGIT E100 under Evonik Roehm house flags, or《Chinese Pharmacopoeia》Two polyacrylic acid recorded of version in 2010
Resin variety, entitled polyacrylic resin IV acrylic resin product；EUDRAGIT E100 mean molecule quantities about 150,
000 dalton, viscosity (20 DEG C) are 10cP, and refractive index 1.38, density 0.815g/cm3, obtained alkali number is every gram of polymer
180mg KOH；
Described amino alkyl methacrylate copolymer dosage is 20-60 parts by weight；
The plasticiser includes citric acid alkyl esters, acetyl tributyl citrate Arrcostab, triacetyl glycerine, O-phthalic dialkylaminobenzoic acid
Ester, sebacic acid alkyl esters, sucrose ester, sorbitol ester, and Macrogol 4000 are to 20,000.Preferable plasticiser is citric acid three
Ethyl ester, ATEC, dibutyl sebacate, triacetyl glycerine；Described plasticiser dosage is 5 to 20 weight
Part；
In the penetrating agent, described two above multicomponent alcoholics compounds are combined as 1,2-PD, polyethylene glycol 400.
Described at least one newborn acid compounds are：Polylactides are lactic acid, ethyl lactate.
Described at least one C6-C18 fatty acid ester compounds are：Fatty acid ester compound isopropyl myristate
(IPM)。
4. according to a kind of percutaneous absorption patch described in claim 3, it is characterised in that：The penetrating agent includes C6-C18 fat
Fat acid compounds, C6-C18 aliphatic alcohols compound and terpenoid.
5. according to a kind of percutaneous absorption patch described in claim 4, it is characterised in that：The C6-C18 fatty acids chemical combination
Thing is capric acid, laurate, myristic acid and oleic acid；C6-C18 aliphatic alcohols compound is decyl alcohol, laruyl alcohol and oleyl alcohol；Terpene
Compound is eucalyptus oil, limonene, terpinol.
6. according to a kind of percutaneous absorption patch described in claim 1-5, it is characterised in that：The drug storing layer further comprises
Moisturizing plasticizer (D)；Described moisturizing plasticizer refers at least one polyvinylpyrrolidone, or polyvinylpyrrolidone/
Vinyl acetate copolymer, or ammonio methacrylate copolymer；Moisturizing plasticizer consumption is 0-20 parts by weight.
A kind of 7. percutaneous absorption patch according to claim 6, it is characterised in that：Described polyvinylpyrrolidone refers to
The polymer made of NVP monomer；The molecular weight of polyvinylpyrrolidone is from 2000 to 2500000 dongles
In the range of；Described polyvinylpyrrolidone//vinyl acetate copolymers refer to by polyvinylpyrrolidone monomer and second
Polymer made of sour ethene alicyclic monomer；Wherein, polyvinylpyrrolidone weight accounts for 60%, and the weight of vinyl acetate resin accounts for
40%；Described ammonio methacrylate copolymer refers to ethyl acrylate, methyl methacrylate and metering system
The copolymer that sour trimethyl ammonium chloride base acetate monomer is copolymerized by way of radical polymerization；The moisturizing plasticizer consumption
For 0-10 parts by weight.
A kind of 8. percutaneous absorption patch according to claim 7, it is characterised in that：The molecular weight of polyvinylpyrrolidone exists
In the range of 28000 to 1500000 dalton；Described ammonio methacrylate copolymer refer to ethyl acrylate,
Methyl methacrylate and methacrylic acid trimethyl ammonium chloride base acetate monomer in proportion (1:2:0.1)(Eudragit RL
Or (1 100):2:0.2) copolymer that (Eudragit RS 100) is copolymerized by way of radical polymerization；Moisturizing is plasticized
Agent initial content is 0 to 5 parts by weight.
A kind of 9. percutaneous absorption patch according to claim 8, it is characterised in that：The molecular weight of polyvinylpyrrolidone exists
In the range of 1,000,000 to 1,500,000 dalton.
A kind of 10. percutaneous absorption patch according to claim 6, it is characterised in that：The PVP products of various grades are purchased from
BASF AG (Ludwigshafen, Germany), or ISP companies (Wayne, New Jersey, USA)；The title of its commodity point
Wei not Kollidon series or Plasdone series；The PVP product lines of Kollidon under one's name include respectively：K-12PF (molecules
Amount=2,000-3,000)；K-17PF (molecular weight=7,000-11,000)；K-25 (molecular weight=28,000-34,000)；K-
30 (molecular weight=44,000-54,000)；With K-90 (molecular weight=1,000,000-1,500,000)；Plasdone is under one's name
PVP product lines include respectively：K-12 (molecular weight=4,000)；K-17 (molecular weight=10,000)；K-25 (molecular weight=34,
000)；K-29/32 (molecular weight=58,000)；With K-90 (molecular weight=1,300,000)；Preferable polyvinylpyrrolidone bag
Include Kollidon K-30, K-90 and Plasdone K-29/32, and K-90；
Described polyvinylpyrrolidone//vinyl acetate copolymers product be purchased from BASF AG (Ludwigshafen,
), or ISP companies (Wayne, New Jersey, USA) Germany.The title of its commodity be respectively Kollidon VA64 or
Plasdone S-630；Kollidon VA64 molecular weight is 40,000；Plasdone S-630 molecular weight in 24,000-30,
000；
Described ammonio methacrylate copolymer includes the product E udragit under Evonik Roehm exabytes
RL100, RLPO and RS100, RSPO.Can be with the presence of chlorion；Mean molecule quantity：150000 dalton (gram/mol)；Viscosity
(20 DEG C) are up to 15Cp, refractive index：1.380-1.385.Density：0.815-0.835g/cm3.Wherein, Eudragit RL
The ratio of 100 cation ester groups and neutral alkyl is 1:20, obtained alkali number is every gram of polymer 28.lmg KOH；Eudragit
The ratio of the cation ester groups of RS 100 and neutral alkyl is 1:40, obtained alkali number is every gram of polymer 15.2mg KOH；It is preferred that
Product be Eudragit RL100.
Described ammonio methacrylate copolymer also includes《Chinese Pharmacopoeia》Two polyacrylic acid recorded of version in 2010
Resin variety, there are poly- first ammonium acrylate ester I, poly- first ammonium acrylate ester II acrylic resin product；Preferable product is poly- first
Ammonium acrylate ester II.
Moisturizing plasticizer initial content is 0 to 5 parts by weight.
11. according to any described a kind of percutaneous absorption patch in claim 1-10, it is characterised in that：The drug storing layer enters one
Step includes active medicine (F).
A kind of 12. percutaneous absorption patch according to claim 11, it is characterised in that：Described active medicine (F) is core
Former times class antiviral drugs or pharmaceutically acceptable salt；Active medicine dosage is 0.01-10 parts by weight in parts by weight.
A kind of 13. percutaneous absorption patch according to claim 12, it is characterised in that：Described core former times class antiviral drugs
Including Entecavir, Entecavir hydrate or pharmaceutically acceptable salt；Aldoforwe ester or pharmaceutically acceptable salt；Draw
Meter Fu Ding or or pharmaceutically acceptable salt；Stavudine or pharmaceutically acceptable salt；Active medicine dosage is in parts by weight
For 0.05-5 parts by weight.
A kind of 14. percutaneous absorption patch according to claim 11, it is characterised in that：The active medicine is Entecavir
Or maleic acid Entecavir, it is in parts by weight 0.1-3 parts by weight.
15. according to any described a kind of percutaneous absorption patch in claim 1-14, it is characterised in that：Described back sheet is
Polyethylene, the woven cloth of polypropylene retractility or non-telescoping property, non-woven fabrics, polyethylene, polypropylene, polyethylene terephthalate
Ester polyester polymers, EVAc, vinyl chloride film material, aluminium film；Or urethane, polyurethane foaminess membrane material
Material；Above-mentioned membrane material can be used alone, and can also be formed using a variety of membrane materials are laminated；For membrane material, be l0 μm-
100 μm, be 50 μm -2 for weaving cotton cloth, non-woven fabrics, foaminess carrier, 000 μm.
A kind of 16. percutaneous absorption patch according to claim 15, it is characterised in that：The thickness of back sheet, for membrane material
For, be 15 μm -50 μm, for weaving cotton cloth, non-woven fabrics, foaminess carrier be 100 μm -1,000 μm.
17. according to any described a kind of percutaneous absorption patch in claim 1-16, it is characterised in that：Described protective layer can
To use glassine paper, polyethylene, polypropylene, polyethylene terephthalate polyester, polystyrene resin film, aluminium film, foaming
The film of polyethylene film or expanded polypropylene membrane material or use the laminated film formed of two or more membrane materials in above-mentioned
Material；The thickness of protective layer is 10 μm -200 μm.
A kind of 18. percutaneous absorption patch according to claim 17, it is characterised in that：Described protective layer can use pair
The membrane material carried out silicone surface processing protection film layer, or carried out fluororesin surface processing protection film layer,
Implement the protective layer of embossed surface processing, plasma surface treatment, hydrophilic surface processing, hydrophobic surface treatments etc..
A kind of 19. percutaneous absorption patch according to claim 17, it is characterised in that：Described protective layer is carried out for surface
The polyester film of silicone surface processing, the thickness of protective layer is 15 μm -150 μm.
20. according to a kind of preparation method of any described percutaneous absorption patch of claim 1-19, it is characterised in that including such as
Lower step：Add polyhydric alcohol polymer that active medicine solid dissolving is added into it with the low molecular polylol in penetrating agent first
Remaining penetrating agent solution, plasticiser, amino alkyl methacrylate copolymer, moisturizing plasticizer and cosolvent mix together
Close, be sufficiently stirred, until it is solution complete miscibility, limpid, stood after the completion of stirring；Uniform colloid masking liquid will be obtained using coating
On technique to protective layer material；The condition of temperature of the drying of above-mentioned masking liquid at 40 DEG C -150 DEG C or so, 20-240 minutes or so
Lower progress, to get rid of cosolvent；It is laminated with back sheet again, it is punched, obtains the transdermal patch of three-decker；It is dried containing
The gummy polymer layers weight per unit area of Entecavir is lmg/cm2-100mg/cm2；Sticky polymers containing Entecavir
The thickness of layer is l0 μm -600 μm.
A kind of 21. preparation method of percutaneous absorption patch according to claim 19, it is characterised in that：Penetrating agent is used first
In low molecular polylol add polyhydric alcohol polymer that active medicine solid dissolving is added into remaining penetrating agent solution, plastify
Agent, amino alkyl methacrylate copolymer, moisturizing plasticizer and cosolvent are mixed together, and are sufficiently stirred about 6 hours,
Until it is solution complete miscibility, limpid, stand 15 minutes after the completion of stirring；Composition stands at least 3 hours to 12 hours, until complete
Full degassing；Uniform colloid masking liquid will be obtained using on coating process to protective layer material, described coating process includes coating
Equipment is coated with or hardened coating.Workable coating apparatus includes roll coater, die coating machine, intaglio plate roll coater, reverse roll coater, kiss
Close roll coater, dipping roll coater, bar coater, knife, Bracewell coater；The drying of above-mentioned masking liquid is at 40 DEG C -150 DEG C or so
Carried out under conditions of temperature, 20-240 minutes or so, to get rid of cosolvent；It is laminated with back sheet again, punching, obtain three-layered node
The transdermal patch of structure；The dried gummy polymer layers weight per unit area containing Entecavir is 2mg/cm2-80mg/cm2；
The thickness of gummy polymer layers containing Entecavir is 30 μm -300 μm.
22. according to a kind of preparation method of any described percutaneous absorption patch of claim 20-21, it is characterised in that：It is described
Cosolvent be the dissolving that can help active medicine Entecavir, and with amino alkyl methacrylate copolymer, and conduct
The polyethylene pyrrole alkanone of moisturizing plasticizer, either polyvinylpyrrolidone//vinyl acetate copolymers or quaternary amine ylmethyl third
The compatible low boiling point organic solvent of olefin(e) acid ester copolymer, dosage are 10-90 parts by weight in parts by weight.
A kind of 23. preparation method of percutaneous absorption patch according to claim 22, it is characterised in that：The cosolvent is
The mixture of acetone, ethyl acetate and absolute ethyl alcohol or these organic solvents.Dosage is 20-70 parts by weight in parts by weight.
A kind of 24. preparation method of percutaneous absorption patch according to claim 23, it is characterised in that：The cosolvent is
30-60 parts by weight.
25. treatment Chronic HBV virus infection is being prepared according to a kind of any described percutaneous absorption patch of claim 1-19
Application in medicine.
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|---|---|---|---|---|
| CN108079386A (en) * | 2018-03-05 | 2018-05-29 | 涂青山 | A kind of bacteria cellulose composite forming material and preparation method thereof |
| CN113616538A (en) * | 2021-08-11 | 2021-11-09 | 中山市天图精细化工有限公司 | Pore-astringing composition film spraying agent and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101002786A (en) * | 2006-01-17 | 2007-07-25 | 周亚伟 | Plaster for treating hepatitis B, and its preparing method |
| CN101787026A (en) * | 2010-01-08 | 2010-07-28 | 福建广生堂药业有限公司 | Amorphous entecavir p-toluenesulfonate salt and preparation method and medicament application thereof |
| WO2012048455A1 (en) * | 2010-10-12 | 2012-04-19 | 武汉大学 | Transdermal absorption patch of antiviral drug and its preparation method |
-
2017
- 2017-08-09 CN CN201710675659.0A patent/CN107441066B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101002786A (en) * | 2006-01-17 | 2007-07-25 | 周亚伟 | Plaster for treating hepatitis B, and its preparing method |
| CN101787026A (en) * | 2010-01-08 | 2010-07-28 | 福建广生堂药业有限公司 | Amorphous entecavir p-toluenesulfonate salt and preparation method and medicament application thereof |
| WO2012048455A1 (en) * | 2010-10-12 | 2012-04-19 | 武汉大学 | Transdermal absorption patch of antiviral drug and its preparation method |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108079386A (en) * | 2018-03-05 | 2018-05-29 | 涂青山 | A kind of bacteria cellulose composite forming material and preparation method thereof |
| CN108079386B (en) * | 2018-03-05 | 2020-12-15 | 涂青山 | Bacterial cellulose composite forming material and preparation method thereof |
| CN113616538A (en) * | 2021-08-11 | 2021-11-09 | 中山市天图精细化工有限公司 | Pore-astringing composition film spraying agent and preparation method thereof |
| CN113616538B (en) * | 2021-08-11 | 2023-02-28 | 中山市天图精细化工有限公司 | Pore-astringing composition film spraying agent and preparation method thereof |
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| Publication number | Publication date |
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| CN107441066B (en) | 2019-03-15 |
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Address after: Room 116, Floor 1, Transportation Bureau Building, No. 95, Yingbin Avenue, Huacheng Street, Huadu District, Guangzhou, Guangdong Province, 510801 Patentee after: Guangdong Iconas Biomedical Technology Co.,Ltd. Patentee after: Yang Mingjing Address before: 515063 in Rongsheng science and Technology Park, University Road, Shantou City, Guangdong Province Patentee before: RUNBIO BIOTECH Co.,Ltd. Patentee before: Yang Mingjing |