CN107441066B - 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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- CN107441066B CN107441066B CN201710675659.0A CN201710675659A CN107441066B CN 107441066 B CN107441066 B CN 107441066B CN 201710675659 A CN201710675659 A CN 201710675659A CN 107441066 B CN107441066 B CN 107441066B
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- percutaneous absorption
- entecavir
- absorption patch
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—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, include 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 compound is constituted promotees infiltration system, clinical requirement drug transdermal rate can not only be better met, and it can match with the amino alkyl methacrylate copolymer transdermal matrix containing plasticiser, make patch under room temperature and/or body temperature there is enough bonding forces to meet clinical demand, does not need in the laminated additional adhesion layer of chip surface.Transdermal drug delivery system preparation process of the invention is relatively easy, and transdermal release rate is high but also has been able to 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, in particular to Entecavir is transdermal
Absorption patch and its preparation method and application.
Background technique
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
About 93,000,000 people of some Patients with Chronic HBV Infection, wherein patient is about for chronic hepatitis B (chronic hepatitis B, CHB)
20000000.The drug 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 the main means for treating chronic hepatitis B, and principle is by blocking or persistently pressing down
The duplication of hepatitis B viruses (HBV) processed in vivo, to mitigate or terminate liver inflammation, necrosis and fibrosis lesion, prevent lesion to
Liver function decompensation, cirrhosis, 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 chronic hepatitis B patient that the current World Health Organization and various countries' guide are recommended 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
Duplication can be melted into active triphosphate by phosphoric acid in the cell, and with HBV reverse transcriptase natural substrate triphosphoric acid deoxidation
Guanosine competition generates drug effect.Entecavir is compared with other nucleosides (acid) class drugs, the incidence with Resistance mutation
It is low, the most strong and moderate feature of antivirus action.U.S. FDAs in 2005 and state food pharmaceuticals administration general bureau
(CFDA) approval Entecavir tablet (trade name: Bo Luding, Bristol-Myers Squibb Co.) is treated for CHB in succession.
The chemical name of Entecavir is 2- amino -9- [(1S, 3R, 4S) -4- hydroxyl -3- methylol -2- methylene amyl] -
1,9- dihydro -6H- purine-6-one, structural formula are as follows:
Molecular formula C12H15N5O3, molecular weight 277.3 usually contain a crystallization water, monohydrate molecular formula
C12H15N5O3H20, molecular weight 295.3.Entecavir (entecavir) bulk pharmaceutical chemicals are white to off-white powder, slightly soluble
Yu Shui, solubility 2.4mg/mL.Solubility increases in acid or alkaline aqueous solution.
But it need to be taken orally 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 empty stomach medication is absorbed to enhance it, this just exacerbates the adverse reaction of Entecavir, such as Nausea and vomiting, abdomen
Bitterly, diarrhea, abdominal discomfort and indigestion etc. cause patient compliance poor, and therapeutic effect is bad.In addition, Entecavir is discontinued
After will appear rebound phenomenon, lead to palindromia, or even hepatic failure occurs, prognosis is bad.Further more, current Oral administration is also
There is blood drug concentrations the problem of apparent fluctuation occurs with time graph.That is, when drug in blood
Concentration it is too low when, it is difficult to give full play to curative effect；And poison can be generated due to overdose when the excessive concentration of drug in blood
Property, it increases burden to body.Meanwhile there is also gastrointestinal tracts to enzymatic hydrolysis of drug and liver first-pass effect etc. for oral administration mode
Problem, so that drug effect reduces.If can be administered to a patient by way of cutaneous penetration can extend releasing for Entecavir
The medicine time improves bioavilability, reduces adverse drug reaction, reduces the stimulation of administration number of times and drug to gastrointestinal tract, in turn
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 arrive and 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 mentioning in disclosed embodiment
Go out and patch has been fixed on patient skin with facilitating in the laminated additional adhesion layer in Entecavir percutaneous absorption patch surface.But
Additional adhesion layer not only limits the percutaneous rate of antiviral drugs, and increase patch processing and manufacturing difficulty and at
This.In addition, main penetrating agent Laurocapram (Azone) used by patent in terms of pharmacological activity and safety 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)
Sticking matrix is well known for transdermal delivery device.US patent 5993849, which discloses, a kind of for skin and transdermal to be controlled
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.It is applicable to nicotine, 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), the cutaneous penetration of naloxone and vitamin A and salicylic acid and its mixture.But the patent
Disclosed system to disclose any these drugs that are related to there is no comprising any penetrating agent for mentioned drug
Specific embodiment, related drug 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 is further introduced into drug on this basis and relevant penetrating agent is still faced with
All various challenges such as sticky insufficient and cold flow.Do not have yet with amino alkyl methacrylate copolymer at present
(EUDRAGIT E100) puts into clinical application as the patch of transdermal matrix.
For the deficiency that existing program is exposed, the invention solves technical solution include screening and methacrylic acid
The plasticiser pharmaceutically received and the penetrating agent combination that aminoalkyl ester copolymer (EUDRAGIT E100) matches are used for core
The transdermal matrix of glycosides (acid) class antiviral drugs, before improving embodiment it is existing viscosity is insufficient and processing difficulties etc. are asked
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
It closes, and the ternary that at least one newborn acid compounds or at least one C6-C18 fatty acid ester compound are constituted promotees infiltration system
Not only show and meet clinical requirement drug transdermal rate, but also can be copolymerized with the amino alkyl methacrylate containing plasticiser
Object transdermal matrix matches, and patch is made under room temperature and/or body temperature to there is enough bonding forces to meet clinical demand.No
It needs in the laminated additional adhesion layer of chip surface.The preferred embodiment of the invention has processing technology simplicity, equipment requirement
The advantages that not high, easy to use suitable for industrialized production and product.
Summary of the invention
A kind of percutaneous absorption patch, the percutaneous absorption patch includes: back sheet, drug storing layer and protective layer.Wherein, medicine is store
Layer include:
(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 free radical polymerization
It is copolymerized.The copolymer of this definition under one's name, the copolymer include the EUDRAGIT under Evonik Roehm house flag
E100, or " Chinese Pharmacopoeia " version two polyacrylic resin kinds recorded in 2010, entitled polyacrylic resin IV's
Acrylic resin product.About 150,000 dalton (gram/mol) of EUDRAGIT E100 average molecular weight, 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 with the film coating or framework material as drug by pharmaceutical industry.
Heretofore described amino alkyl methacrylate copolymer initial content is 10-90 parts by weight, preferably
15-70 parts by weight, and more preferably 20-60 parts by weight.
The substance for being suitable as plasticiser usually has 100 to 20, the molecular weight between 000, and contains 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 are to 20,000.Preferred plasticiser is triethyl citrate, acetyl triethyl citrate, decanedioic acid
Dibutyl ester, triacetyl glycerine.Preferred plasticiser is triethyl citrate.
The additive amount of plasticiser can be according to the physical property feature and packet of amino alkyl methacrylate copolymer
Include the antiviral drugs certain drug dosage form including Entecavir and penetrating agent requirement be adjusted, to make patch in room temperature
And/or enough bonding forces are obtained under body temperature and not will lead to the generation of cold flow.In general, 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, the plasticiser initial content is 1
To 30 parts by weight, preferably 3 to 25 parts by weight.More preferable 5 to 20 parts by weight.
Penetrating agent refers to that one kind well known in the art can overcome skin barrier effect, increases drug transdermal rate or increase medicine
The substance of the transdermal quantity of object.The penetrating agent (C) in the present invention, is combined, and extremely by two or more multicomponent alcoholics compounds
A kind of few newborn acid compounds, or at least one fatty acid ester compound are composed.
The polyol compound includes 1,2-PD, 1,3-PD, 1,2- butanediol, 1,3-BDO, and 1,
The low-carbon multis such as 4- butanediol alcoholic compound and polyethylene glycol 200,400,600, polypropylene glycol 200,400,600 waits under room temperature
For the polyhydric alcohol polymer of liquid.Preferred two or more multicomponent alcoholics compound groups are combined into 1,2-PD, polyethylene glycol
400。
The described newborn acid compounds of at least one include: lactic acid, calcium lactate, sodium lactate, zinc lactate, ferrous lactate, cream
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.Preferred polylactides are lactic acid, ethyl lactate.
At least one C6-C18 fatty acid ester compound includes: isopropyl myristate (IPM), polyethylene glycol
Monolaurate (PEGML), propylene glycol monolaurate (PGML), Propylene glycol monodecanoate (PGMC), glyceryl monolaurate
(GML), Monoolein (GMO), ethyl oleate.Preferred fat acid esters compound is propylene glycol monolaurate
(PGML), isopropyl myristate (IPM).More preferable fatty acid ester compound isopropyl myristate (IPM).
Other well known penetrating agent, such as C6-C18 fatty acid compound such as capric acid, lauric acid, myristic acid and oil
Acid, C6-C18 fatty 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 the antiviral drugs dissolved including Entecavir, also has to the drug certain
Mechanism.Two kinds of multicomponent alcoholics compound collaborations, which are used, 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 rouge
Fat acid esters compound, which merges, to be used, and is obviously increased to the osmotic effect of the antiviral drugs including Entecavir.If
Penetrating agent only selects multicomponent alcoholics compound or newborn one of acid compounds or fatty acid ester compound, then dissolution and
Osmosis will be obvious insufficient, can not achieve the desired results.More importantly preferred embodiment of the invention kind is used
Two kinds of multicomponent alcoholics compounds and at least one newborn acid compounds, or composed by least one fatty acid ester compound
Ternary rush infiltration system, which not only shows, meets clinical requirement drug delivery rate, but also can be with the methacrylic acid ammonia containing plasticiser
Base alkyl ester copolymer transdermal matrix matches, so that patch is made to have enough bondings under room temperature and/or body temperature
Power and the generation that not will lead to cold flow.
Two kinds of multicomponent alcoholics compound compounds of the present invention, at least one newborn acid compounds, or it is at least one
The combination penetrating agent usage amount of C6-C18 fatty acid compound or at least one fatty acid ester compound is respectively as follows: low-carbon
Polyol compound is 1-40 parts by weight；Polyhydric alcohol polymer 1-20 parts by weight；At least one cream acid compounds are 0.1-15
Parts by weight, or at least one C6-C18 fatty acid ester compound 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 cream acid compounds are 0.5-10 parts by weight, or at least one
Kind C6-C18 fatty acid compound is 0.5-10 parts by weight, or at least one fatty acid ester compound is 0.5-10 weight
Part.
Percutaneous absorption patch of the invention further comprises moisturizing plasticizer (D).Moisturizing plasticizer is further to improve
The viscosity and cohesive strength for adjusting amino alkyl methacrylate copolymer transdermal matrix, transdermal matrix appearance is avoided to peel off,
Phenomena such as cold flow, improves stability of the drug during storage and use, and comfort when wearing.It reduces or eliminates transdermal
Irritation of the device to skin.Moisturizing plasticizer be usually pharmacy industry as auxiliary material it is receptible and compatible with this system
Any one of hydrophilic high mol.The moisturizing plasticizer refers at least one polyvinylpyrrolidone or polyethylene pyrrole
Pyrrolidone/vinyl acetate copolymer or ammonio methacrylate copolymer.
The polyvinylpyrrolidone (PVP) refers to the polymer made of n-vinyl pyrrolidone monomer.Poly- second
It is excellent in the range of from 2000 to 2500000 dalton (gram/mol) (being given as weight average molecular weight) of molecular weight of alkene pyrrolidone
The molecular weight of the polyvinylpyrrolidone of choosing is in the range of dalton (gram/mol) from 28000 to 1500000.More preferably
The molecular weight of polyvinylpyrrolidone is in the range of dalton (gram/mol) from 1,000,000 to 1,500,000.It is various etc.
The PVP product of grade be purchased from BASF AG (Ludwigshafen, Germany) or ISP company (Wayne, New Jersey,
USA).The title of its commodity is respectively Kollidon series or Plasdone series.The PVP product line of Kollidon under one's name point
It does 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 line of Plasdone under one's name respectively include: 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).
Preferred polyvinylpyrrolidone includes Kollidon K-30, K-90 and Plasdone K-29/32, and K-90.More preferably
Polyvinylpyrrolidone is Plasdone K-90.
The 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 company (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.
The ammonio methacrylate copolymer refers to ethyl acrylate, methyl methacrylate and methyl-prop
Olefin(e) acid trimethyl ammonium chloride base acetate monomer (1:2:0.1) (Eudragit RL 100) or (1:2:0.2) by a certain percentage
Copolymer made of (Eudragit RS 100) is copolymerized by way of free radical polymerization.
The ammonio methacrylate copolymer includes the product E udragit under Evonik Roehm company name
RL100, RLPO and RS100, RSPO.It can be with the presence of chloride ion；150000 dalton (gram/mol) of average molecular weight；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, and obtained alkali number is every gram of polymer 28.lmg KOH；Eudragit RS 100
The ratio of cationic ester group and neutral alkyl is 1:40, and obtained alkali number is every gram of polymer 15.2mg KOH.The quaternary amine
Methacrylate copolymer further includes " Chinese Pharmacopoeia " version two polyacrylic resin kinds recorded in 2010, there is poly- first
Ammonium acrylate ester I, the acrylic resin product of poly- first ammonium acrylate ester II.Preferred 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 preferable 0
To 5 parts by weight.Ideal Medicated Permeation rate is then extremely difficult to beyond the range and keeps obtaining enough bonding forces.
Percutaneous absorption patch of the invention further comprises active medicine (E).
The 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.The pharmaceutically acceptable entecavir salt includes: maleic acid Entecavir.Active medicine is preferably Entecavir.
Preferred active medicine dosage is 0.01-10 parts by weight in parts by weight in the present invention.The present invention is more preferably living
Property drug usage amount is 0.05-5 parts by weight in parts by weight.The most preferred active medicine usage amount of the present invention is in parts by weight
0.1-3 parts by weight.Transdermal amount is not able to satisfy the treatment effective dose of the medicament if its usage amount is too low；On the contrary, if making
Dosage is excessively high, then as in active medicine Entecavir in the present invention system really with existing for over-saturation dissolved state,
It is easy to cause active medicine crystallization to be precipitated, and then influences the transdermal release rate of active medicine Entecavir.In addition, excessively high
Drugloading rate is also inappropriate from the point of view of economy.
Percutaneous absorption patch structure in the present invention is lamination layer structure, includes: 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 ethylene, polypropylene or non-telescoping property, non-woven fabrics, polyethylene, polypropylene, polyethylene terephthalate
The membrane materials such as the polyester polymers such as ester, ethylene vinyl acetate copolymer, vinyl chloride, aluminium film.Or the foaming such as urethane, polyurethane
Property membrane material.Above-mentioned membrane material can be used alone, and also can be used that a variety of membrane materials are laminated to be formed.Such as polyethylene-aluminium-is poly-
Ethylene compound film material.In turn, electrostatic is accumulated on carrier in order to prevent, can also be in above-mentioned woven fabric, the nonwoven for constituting back sheet
Contain antistatic agent in the materials such as cloth, film.In addition, it is good anchoring properties with adhesive phase in order to obtain, it can be by non-woven fabrics
Or woven cloth is mixed into gummy polymer layers, then combines 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 porosity pieces such as woven fabric, non-woven fabrics, foaminess carriers
Material, usually 50 μm -2,000 μm, preferably 100 μm -1,000 μm.
Protective layer of the present invention refers to the general protective film layer in patch field.As protective 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 films of the materials such as polyethylene film or expanded polypropylene film or use film made of two or more membrane materials are laminated among the above
Material.The protective film layer that silicone surface processing has been carried out to above-mentioned membrane material also can be used in the present invention, or has carried out fluorine tree
Rouge surface treatment protective film layer, implement embossed surface processing, plasma surface treatment, hydrophilic surface handle, it is hydrophobic
Property surface treatment etc. protective film layer etc..The preferred surface of the protective film layer of transdermal patch of the present invention carries out at silicone surface
The polyester film of reason.The thickness of protective film layer is usually 10 μm -200 μm, and preferably 15 μm -150 μm.
The present invention also provides the preparation methods of above-mentioned transdermal patch.Preparation method includes the following steps: first with rush
Low molecular polylol in penetration enhancer adds polyhydric alcohol polymer to dissolve active medicine solid, adds remaining penetrating agent solution,
Plasticiser, amino alkyl methacrylate copolymer, moisturizing plasticizer and cosolvent are mixed together, and are sufficiently stirred about 6
Hour, until solution complete miscibility, limpid, standing 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, the coating process packet
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 temperature of choosing and progress, such as 40 DEG C -150 DEG C or so of temperature under drying time, under conditions of 20-240 minutes or so
Fallen cosolvent to remove.Laminated with back sheet again, punching obtains the transdermal patch of three-decker.Contain grace after drying
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 gummy polymer layers containing Entecavir after drying, more preferably 30 μm of -300 μ
m.Gained transdermal patch can be put into appropriate packaging used to store, such as paper bag and/or metallic foil bag, be saved in transdermal control
When treatment.
Used cosolvent refers to that one kind well known in the art can help active medicine grace to replace to the present invention during the preparation process
The dissolution of card Wei, and with amino alkyl methacrylate copolymer, and as the polyethylene pyrrole alkanone of moisturizing plasticizer, or
Polyvinylpyrrolidone//vinyl acetate copolymers or ammonio methacrylate copolymer it is compatible low boiling point it is organic
Solvent.Such as the mixture of acetone, ethyl acetate and dehydrated alcohol or these organic solvents.Heretofore described cosolvent is
Absolute alcohol.Initial content is 10-90 parts by weight in parts by weight, preferably 20-70 parts by weight, more preferably 30-60 weight
Part.
The present invention uses two or more multicomponent alcoholics compounds to combine, and at least one newborn acid compounds, or at least
A kind of ternary rush infiltration system that C6-C18 fatty acid ester compound is constituted, can not only better meet clinical requirement drug transdermal
Rate, 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, does not need laminated additional viscous in chip surface
Attached layer.Transdermal patch of the present invention has many advantages, such as that processing technology is easy, equipment requirement is not high, easy to use.
Detailed description of the invention
Fig. 1 is the schematic cross-section of patch.Wherein, 1 be back sheet, 2 be drug storing layer (gummy polymer layers), 3 be protection
Layer (protective film layer).
Specific 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 shows the signals of the transdermal drug delivery system for the Entecavir prepared and manufactured in embodiment 1 (TCDS) patch
Property sectional view comprising back sheet (1), drug storing layer (2), protective layer (3).
Embodiment 1
Entecavir 0.8g, propylene glycol 11.2g, polyethylene glycol 400 6.4g is taken to be put into togerther in triangular flask, bottle sealing,
In stirring 6 hours on magnetic stirring apparatus, until solution complete miscibility, limpid, standing 15 minutes after the completion of stirring.By lactic acid
2.8g, triethyl citrate 13.5g, amino alkyl methacrylate copolymer E100 40g, cosolvent dehydrated alcohol 72g mono-
It rises and is added in the triangular flask of solubilized solution medical fluid, bottle sealing is stood after the completion of stirring in stirring 12 hours on magnetic stirring apparatus
It is stand-by after 30 minutes.It will obtain what uniform colloid scraper coating machine or hardened coating were handled to silicone surface
It on PET polyester film protective layer material, is dried 40 minutes under the conditions of 80 DEG C and falls cosolvent to remove, the viscosity after making drying is poly-
The Entecavir content closed in nitride layer is about 0.2/cm2.After cooling again with back sheet (SCOTCH PAK 1109,3M,
St.Paul, US) pressing, punching, be cut into the size of 5cm X 5cm, pack up to drug storing layer with a thickness of 110 μm or so three
The transdermal patch of layer structure.
24 hours dermal penetration rates of Entecavir patch use pig ear skin, are expanded by Valia-chien two-chamber osmotic
It dissipates pond and high performance liquid chromatography (HPLC) is evaluated.
Fresh pig ear takes the outer Middle face of ear to remove the skin of the cartilage and internal layer among ear to the position of have sharp ears,
Subcutaneous extra fat to be cut, cuts flat whole, is then cut into the rounded nubs of diameter 20mm, subzero 21 DEG C of refrigerators save backup,
Using preceding immersion physiological saline 1h, can be used with filter paper suck dry moisture.
Pig ear skin is tightly attached between two Room of VALIA-CHIEN osmotic cell, skin corium is towards receiving chamber, cuticula face paste
Upper Entecavir transdermal patch fixes the twoport of two Room with spring clip, and 0.2mol/L phosphate-buffered is added in receiving chamber
Liquid (PH 7.4) 3.4ml controls the water temperature in osmotic cell interlayer at 32 ± 0.5 DEG C, electromagnetic agitation revolving speed 400r/min, by rule
The penetrating fluid for taking out 800 μ l after fixed 24 hours from receiving chamber measures the transdermal of Entecavir in 24 hours penetrating fluids with HPLC method
Rate.The results are shown in Table 1.
Entecavir transdermal patch surface viscosity is investigated by 180 ° of peel strengths.Peel strength refers to pressure appropriate
The ability of pressure-sensitive adhesive product and the resistance interfacial separation showed between maxxaedium after power and time are pasted.
Before test, patch is removed into packaging material, place 2 hours at room temperature without overlapping or more.By the patch back side
It is fixed on breadboard with double-sided adhesive, 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 exists.Test sample is viscous
After patch, tested after placing 20-40 minutes at room temperature.By 180 ° of the doubling of polyester film free end, film free end and
Left and right is held on testing machine breadboard respectively.Because being consistent release surface with testing machine line.Testing machine with 300mm/min ±
10mm/min is continuously removed, and the peel strength result that testing machine is shown is recorded after removing.For transdermal patch, removing
Intensity should be within the scope of 0.24-2.50kN/m.The results are shown in Table 1.
Comparative example 1
Referring to the embodiment 1 in world patent WO2012048455A1, amino alkyl methacrylate copolymerization is weighed
Object EUDRAGIT E100 11.84g, is dissolved in advance with 17.76g ethyl acetate, and amino alkyl methacrylate copolymerization is made
Object solution viscosity 29.6g (it is 40% that EUDRAIT E100, which consolidates object feed weight ratio), is added antiviral drug of Entecavir
0.08g, transdermal enhancer Laurocapram 1.44g, eucalyptus oil 0.96g and propylene glycol 1.42g mixture and solvent ethyl acetate 16g
It is put into togerther in triangular flask bottle, bottle sealing, is stirred 15 hours on magnetic stirring apparatus, then stand until bubble collapse.It will obtain
The PET polyester film protective layer material that handles of uniform colloid scraper coating machine or hardened coating to silicone surface
On, then fall cosolvent to remove within dry 2 minutes at drying 2 minutes, 90 DEG C at drying 4 minutes, 60 DEG C at 40 DEG C, it is cooling
It is pressed again with back sheet (SCOTCH PAK 1109,3M, St.Paul, US) afterwards, punching is packed up to drug storage layer with a thickness of 110 μ
The transdermal patch of the three-decker of m or so.24 hours transdermal speed of Entecavir transdermal patch is measured as described in Example 1
Rate and 180 ° of peel strengths.The results are shown in Table 1
Table 1:
| Embodiment 1 | Comparative example 1 | |
| Transdermal release rate (μ g/cm2.h) for 24 hours | 14.08 | 1.13 |
| Peel strength (KN/m) | 0.75 | 0.01 |
Table 1 is the results show that the embodiment of the present invention 1 not only shows high drug transdermal rate, but also peel strength can
To reach 0.75KN/m, this makes patch obtain enough bonding forces under room temperature and/or body temperature.Comparative example is reviewed,
Peel strength only has 0.01KN/m.It is sticky obvious insufficient.It needs in the laminated additional adhesion layer in absorption adhesive patch surface or borrows it
Its auxiliary device could be fixed on the skin.
Comparative example 2
Formula composition is substantially the same manner as Example 1, and penetrating agent is only added propylene glycol and combines with polyethylene glycol 400.By implementation
The method of example 1 is made patch and measures the percutaneous rate of Entecavir transdermal patch.The results are shown in Table 2.
Comparative example 3
Formula composition is substantially the same manner as Example 1, and lactic acid is only added in penetrating agent.Patch is made simultaneously as described in Example 1
Measure the percutaneous rate of Entecavir transdermal patch.The results are shown in Table 2.
Table 2:
| Embodiment 1 | Comparative example 2 | Comparative example 3 | |
| Transdermal release rate (μ g/cm2.h) for 24 hours | 14.08 | 3.22 | 12.31 |
Table 2 is the results show that the comparative example 3 of lactic acid penetrating agent is slightly above only added in the drug transdermal rate of embodiment 1, significantly
The comparative example 2 of penetrating agent is combined with polyethylene glycol 400 higher than addition propylene glycol.When this shows respectively using single penetrating agent,
Because not having synergistic effect, Entecavir mechanism be 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.It presses
The method of embodiment 1 is made patch and measures the 24 hours percutaneous rates and 180 ° of peel strengths of Entecavir transdermal patch.
The results are 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 measure Entecavir transdermal patch 24 hours percutaneous rates and 180 ° removing
Intensity.The results are 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 measures the 24 hours percutaneous rates 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 acetyl triethyl citrate in embodiment 1
Generation.As described in Example 1 be made patch and measure Entecavir transdermal patch 24 hours percutaneous rates and 180 ° removing
Intensity.The results are shown in Table 3.
Table 3:
Table 3 is the results show that can get ideal drug transdermal rate using different types of plasticiser, and remove strong
Degree is located within the scope of 0.31-0.78KN/m, this makes above-mentioned patch 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 measures the 24 hours percutaneous rates 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 measure Entecavir transdermal patch 24 hours percutaneous rates and 180 ° removing
Intensity.The results are shown in Table 4.
Embodiment 8
Formula composition is substantially the same manner as Example 1, and penetrating agent lactic acid is with propylene glycol monolaurate (PGML) in embodiment 1
Substitution.As described in Example 1 be made patch and measure Entecavir transdermal patch 24 hours percutaneous rates and 180 ° stripping
From intensity.The results are 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 24 hours percutaneous rates and 180 ° of peel strengths for measuring Entecavir transdermal patch.The results are shown in Table 4.
Table 4:
Table 4 can get ideal the results show that combining using different types of penetrating agent with propylene glycol with polyethylene glycol 400
Drug transdermal rate, especially propylene glycol, polyethylene glycol 400 and lactic acid and propylene glycol, polyethylene glycol 400 and lactic acid Pork and beans
Cool isopropyl propionate (IPM) penetrating agent combination becomes apparent the rush infiltration effect of drug, can be used as preferred penetrating agent combination.Table 4
All embodiment peel strengths are located within the scope of 0.51-0.75KN/m, this illustrates above-mentioned patch under room temperature and/or body temperature
All have enough bonding forces.
Embodiment 10
Formula composition is substantially the same manner as Example 1, and 40g amino alkyl methacrylate copolymer E100 is changed to
48g.Patch measurement 24 hours percutaneous rates of Entecavir transdermal patch are made as described in Example 1 and 180 ° of removings are strong
Degree.The results are shown in Table 5.
Embodiment 11
Formula composition is substantially the same manner as Example 1, and the additional 1.6g polyvinylpyrrolidone that is added is Plasdone K-90.
Patch measurement 24 hours percutaneous rates of Entecavir transdermal patch 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, additional that 1.6g ammonio methacrylate copolymer RL100 is added.
Patch measurement 24 hours percutaneous rates of Entecavir transdermal patch 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 copolymer E100 is changed to
36g polyacrylic resin IV.Patch is made as described in Example 1 and measures Entecavir transdermal patch 24 hours transdermal speed
Rate and 180 ° of peel strengths.The results are shown in Table 5.
Table 5:
Table 5 is the results show that further addition amino alkyl methacrylate copolymer E100, polyvinylpyrrolidone are
The drug transdermal rate and 180 ° of peel strengths that Plasdone K-90 is obtained are ideal.It is changed to IV pairs of polyacrylic resin
180 ° of peel strengths are affected, but drug transdermal rate and 180 ° of peel strengths are in acceptable range.These embodiments
It is very helpful to inhibiting patch cold flow to occur.
Transdermal drug delivery system preparation process of the invention is relatively easy, and transdermal release rate is high but also has been able to maintain enough
Stability.
Claims (16)
1. a kind of percutaneous absorption patch, includes: protective layer, drug storing layer and back sheet；Wherein, drug storing layer includes:
(A) adhesive；
(B) plasticiser；
(C) penetrating agent；
Wherein described adhesive is by butyl methacrylate, Dimethylaminoethyl Methacrylate and methyl methacrylate
Made of monomer is copolymerized by way of free radical polymerization in 1:2:1 ratioE100, adhesive is in parts by weight
For 15-70 parts by weight；
The plasticiser is in triethyl citrate, dibutyl sebacate, acetyl triethyl citrate, triethylglycerides
Any, plasticiser is 3-25 parts by weight in parts by weight；
The penetrating agent is the propylene glycol, the polyethylene glycol 400 of 3-15 parts by weight and 0.5-10 parts by weight of 5-20 parts by weight
The combination of lactic acid.
2. percutaneous absorption patch according to claim 1, it is characterised in that: the drug storing layer further comprises active medicine (F).
3. percutaneous absorption patch according to claim 2, it is characterised in that: the active medicine (F) is anti-for core former times class
Virus drugs or pharmaceutically acceptable salt；Active medicine dosage is 0.01-10 parts by weight in parts by weight.
4. percutaneous absorption patch according to claim 3, it is characterised in that: the core former times class antiviral drugs includes grace
For card Wei, Entecavir hydrate or pharmaceutically acceptable salt；Aldoforwe ester or pharmaceutically acceptable salt；Lamivudine
Or pharmaceutically acceptable salt；Stavudine or pharmaceutically acceptable salt；Active medicine dosage is 0.05-5 in parts by weight
Parts by weight.
5. a kind of percutaneous absorption patch according to claim 2, it is characterised in that: the active medicine be Entecavir or
Maleic acid Entecavir is in parts by weight 0.1-3 parts by weight.
6. percutaneous absorption patch according to any one of claims 1-5, it is characterised in that: the back sheet is poly- second
Alkene, the woven cloth of polypropylene retractility or non-telescoping property, non-woven fabrics, polyethylene, polypropylene, polyethylene terephthalate are poly-
Ester polymer, ethylene vinyl acetate copolymer, vinyl chloride film material, aluminium film；Or urethane, polyurethane foaminess membrane material；
Above-mentioned membrane material is used alone, or forms a variety of membrane materials are laminated；The thickness of back sheet use membrane material when for l0 μm-
100 μm, be 50 μm -2000 μm when being used in woven fabric, non-woven fabrics, foaminess carrier.
7. percutaneous absorption patch according to claim 6, it is characterised in that: the thickness of back sheet is 15 when using membrane material
μm -50 μm, be 100 μm -1000 μm when being used in woven fabric, non-woven fabrics, foaminess carrier.
8. percutaneous absorption patch described in any one of -7 according to claim 1, it is characterised in that: the protective layer is glass
Paper, polyethylene, polypropylene, polyethylene terephthalate polyester, polystyrene resin film, aluminium film, polyethylene foamed film or
Two or more Film laminateds are laminated among the above for the film of expanded polypropylene membrane material or use；Protective layer with a thickness of
10μm-200μm。
9. a kind of percutaneous absorption patch according to claim 8, it is characterised in that: the protective layer is to the film
The protective film layer of silicone surface processing has been carried out, or carried out the protective film layer of fluororesin surface processing, implemented pressure
Flower surface processing, plasma surface treatment, hydrophilic surface processing, hydrophobic surface treatments protective layer.
10. a kind of percutaneous absorption patch according to claim 8, it is characterised in that: the protective layer is surface progress
Silicone surface processing polyester film, protective layer with a thickness of 15 μm -150 μm.
11. the preparation method of -10 described in any item percutaneous absorption patch according to claim 1, it is characterised in that including as follows
Step: first in penetrating agent propylene glycol and polyethylene glycol 400 active medicine solid dissolved, add lactic acid, plasticiser,E100, moisturizing plasticizer and cosolvent are mixed together, are sufficiently stirred, until it is solution complete miscibility, limpid, it stirs
It is stood after the completion of mixing；Uniform colloid masking liquid will be obtained using on coating process to protective layer material；The drying of above-mentioned masking liquid exists
It is carried out under conditions of 40 DEG C -150 DEG C, 20-240 minutes, falls cosolvent to remove；Laminated with back sheet again, punching obtains three layers
The transdermal patch of structure；The gummy polymer layers weight per unit area containing Entecavir after drying is lmg/cm2-100mg/
cm2；Gummy polymer layers containing Entecavir with a thickness of l0 μm -600 μm.
12. the preparation method of percutaneous absorption patch according to claim 11, it is characterised in that: first in penetrating agent
Propylene glycol and polyethylene glycol 400 dissolve active medicine solid, add lactic acid, plasticiser,E100, moisturizing increase
Modeling agent and cosolvent are mixed together, and 6 hours are sufficiently stirred, until solution complete miscibility, limpid, standing 15 after the completion of stirring
Minute；Composition stands 3 hours to 12 hours, until being thoroughly degassed；Uniform colloid masking liquid will be obtained and use coating process extremely
On protective layer material, the coating process includes coating apparatus coating or hardened coating, and coating apparatus used is selected from roller coating
Machine, die coating machine, intaglio plate roll coater, reverse roll coater, the roll coater that coincide, dipping roll coater, bar coater, knife, spraying coating
Machine；The drying of above-mentioned masking liquid carries out under conditions of 40 DEG C -150 DEG C, 20-240 minutes, falls cosolvent to remove；Again with back
Lining is laminated, and punching obtains the transdermal patch of three-decker；The gummy polymer layers unit area containing Entecavir after drying
Weight is 2mg/cm2-80mg/cm2；Gummy polymer layers containing Entecavir with a thickness of 30 μm -300 μm.
13. the preparation method of the described in any item percutaneous absorption patch of 1-12 according to claim 1, it is characterised in that: described
Cosolvent is the dissolution that can help active medicine Entecavir, and with amino alkyl methacrylate copolymer, and as guarantor
The polyethylene pyrrole alkanone of wet plasticizer perhaps polyvinylpyrrolidone//vinyl acetate copolymers or quaternary amine ylmethyl propylene
The compatible low boiling point organic solvent of acid ester copolymer, dosage are 10-90 parts by weight in parts by weight.
14. the preparation method of percutaneous absorption patch according to claim 13, it is characterised in that: the cosolvent is third
The mixture of ketone, ethyl acetate and dehydrated alcohol or these organic solvents, dosage are 20-70 parts by weight in parts by weight.
15. the preparation method of percutaneous absorption patch according to claim 14, it is characterised in that: the cosolvent is 30-
60 parts by weight.
16. medicine of -10 described in any item percutaneous absorption patch in preparation treatment Chronic HBV virus infection according to claim 1
Application in object.
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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 |
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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 |
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