CN113616625A - Long-acting transdermal patch of rivastigmine - Google Patents
Long-acting transdermal patch of rivastigmine Download PDFInfo
- Publication number
- CN113616625A CN113616625A CN202110985399.3A CN202110985399A CN113616625A CN 113616625 A CN113616625 A CN 113616625A CN 202110985399 A CN202110985399 A CN 202110985399A CN 113616625 A CN113616625 A CN 113616625A
- Authority
- CN
- China
- Prior art keywords
- rivastigmine
- sensitive adhesive
- pressure
- long
- patch
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Neurology (AREA)
- Emergency Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Psychology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A rivastigmine long-acting transdermal patch belongs to the field of pharmacy, and particularly relates to a technology for constructing a rivastigmine long-acting transdermal drug delivery system, wherein the rivastigmine long-acting transdermal drug delivery system is suitable for carrying out rivastigmine transdermal drug delivery at a stable speed for more than 72 hours, and the structure of the rivastigmine long-acting transdermal patch comprises the following layers arranged in sequence: the backing layer, the acrylic pressure-sensitive adhesive layer containing the rivastigmine, the release film for controlling the rivastigmine, the adhesive layer and the protective layer. The rivastigmine transdermal patch provided by the invention has good skin adhesion, small irritation, and better chemical stability and physical stability.
Description
Technical Field
The invention relates to a long-acting transdermal patch of rivastigmine, belonging to the technical field of pharmacy.
Background
Rivastigmine is a cholinesterase inhibitor acting on the central nervous system, and is an active substance used for the treatment of alzheimer's disease and parkinson's disease. The action mechanism is that the cholinergic nerve conduction is promoted by delaying the degradation of acetylcholine by cholinergic neurons. The existing dosage forms of the rivastigmine comprise capsules and transdermal patches, but oral administration of the rivastigmine often causes serious gastrointestinal side effects, so the transdermal patches are the first choice of administration.
In patent application CN 107929267 a, a method for preparing a single day patch of rivastigmine is disclosed, which reduces the gastrointestinal side effects caused by the drug compared to oral administration. However, the nature of one patch per day can cause damage to the stratum corneum due to frequent avulsion, and the damaged stratum corneum often causes the drug permeation amount to be remarkably increased, and on the contrary, toxic and side effects are caused. In patent application CN 107412202 a, a long acting patch of rivastigmine is disclosed, which uses a controlled release membrane with a porosity of 90%, ensuring a steady rate of administration of the active substance over a three day period. In order to achieve a sufficiently stable release of rivastigmine in transdermal patches, a solution is used in which the polymer matrix of the active substance layer does not contain any free hydroxyl or carboxyl groups. However, because the release agent does not contain free carboxyl or hydroxyl, the stability of the weak alkaline drug rivastigmine is difficult to ensure, and the release curve of the release agent is obviously collapsed after 24 hours.
Disclosure of Invention
In order to solve the problem that the release curve of the sustained release preparation is obviously collapsed, the invention aims to provide a sustained transdermal drug delivery system of the rivastigmine, which has good stability, applies the active substance at a linear rate within 72 hours and has small skin irritation. The present study ensured the stability of the drug by first using a pressure sensitive adhesive containing carboxyl groups, followed by modification of the release behavior of the drug from the matrix by the addition of resins. On the basis, the EVA controlled release membrane is confirmed, and the approximately linear permeation curve is ensured. Through the research, the rivastigmine long-acting transdermal system which has high drug stability and maintains approximate linear penetration within 72 hours is obtained.
The technical scheme adopted by the invention for solving the technical problems is as follows: a long acting transdermal patch of rivastigmine comprising layers arranged in the following order: a back lining layer, a medicine-containing pressure-sensitive adhesive layer, a controlled release film, an adhesive layer and a protective layer;
the method is characterized in that: the back lining layer is a polyester film;
the pressure-sensitive adhesive in the medicine-containing pressure-sensitive adhesive layer is acrylic pressure-sensitive adhesive containing carboxyl groups; in the medicine-containing pressure-sensitive adhesive layer, the weight of the acrylic acid pressure-sensitive adhesive is 30-49.9%; 30-40% by weight of rivastigmine; 10-30% by weight of polyacrylic resin; DL-alpha-tocopherol is 0.1% by weight; wherein the concentration of the DL-alpha-tocopherol solution is 2 mg/mL;
the controlled release film is an EVA film with the mass fraction of vinyl acetate monomer of 19%;
the adhesive layer contains 99.80-99.89% of silicone pressure sensitive adhesive, 0.01-0.1% of dimeticone and 0.1% of DL-alpha-tocopherol; wherein the concentration of the DL-alpha-tocopherol solution is 2 mg/mL;
acrylic pressure sensitive adhesive containing carboxyl groups in the polymer matrix;
the adhesive layer is an amino compatible series of organic silicon pressure-sensitive adhesive;
acrylic pressure sensitive adhesives containing free carboxyl groups, preferably
87-2852、
87-2677、
87-235A.
Polyacrylic resin containing nitrogen groups in the pressure-sensitive adhesive layer containing the medicine is preferably Eudragit E100 and/or Eudragit EPO.
The pressure sensitive adhesive layer containing medicine may be added with penetration promoter in 0-10 wt%, preferably azone, carbitol, oleic acid, etc. The preferable scheme is that no penetration enhancer is added.
The controlled release membrane is a membrane for controlling the release of rivastigmine, preferably CoTranTM9712 of (1); experiments prove that other controlled-release films cannot achieve the effect of controlled release for 72 hours so as to deliver the rivastigmine transdermally at a constant speed.
The silicone pressure sensitive adhesive is preferably BIO-PSA of DOW CORNINGTM7-4202 and 7-4302. The silicone adhesive of the amine-based compatible series can be replaced by an acrylic pressure sensitive adhesive containing free carboxyl groups, preferably
87-2852、
87-2677、
87-235A.
The backing film of the long-acting patch should be polyester film, preferably 3M ScotchpakTM1109,9723,9736,9738.
Transdermal patches exhibit substantially linear skin penetration of the active agent for a period of at least 72 hours as measured by the in vitro skin penetration test.
The drug loading of the rivastigmine patch is 23-30 mg.
The size of the rivastigmine patch is 5-15cm2。
The thickness of the drug-containing layer of the rivastigmine patch is 90-120 μm.
The thickness of the rivastigmine patch adhesive layer is 15-25 μm.
The sustained-sticking time of the rivastigmine long-acting patch is more than 72 hours.
A long-acting transdermal patch of rivastigmine comprises 4.0-6.5g of acrylic ester pressure sensitive adhesive containing carboxyl groups, 1.3-1.5g calculated by rivastigmine, 2ml of DL-alpha-tocopherol solution of 1.9mg/ml and 0.2-1.0g of polyacrylic resin.
A preparation method of a long-acting transdermal patch of rivastigmine comprises the following steps:
(1) proportionally taking acrylate pressure-sensitive adhesive containing carboxyl groups, rivastigmine, polyacrylic resin and DL-alpha-tocopherol solution, and mixing uniformly; standing to obtain a drug-loaded pressure-sensitive adhesive; coating on an anti-sticking layer to obtain a patch, drying and compounding a backing film;
(2) mixing the organic silicon pressure-sensitive adhesive, the 1, the dimeticone and the DL-alpha-tocopherol in proportion until the mixture is uniform; coating on the anti-sticking layer to form a patch, drying, and compounding a controlled release membrane;
(3) the medicine-containing layer and the adhesive layer are spliced together to obtain the rivastigmine long-acting transdermal patch.
The invention has the beneficial effects that: according to the invention, the acrylic pressure-sensitive adhesive containing free carboxyl is mixed with the polyacrylic resin, so that the advantages of the acrylic pressure-sensitive adhesive and the polyacrylic resin are integrated, the solubility of the rivastigmine in the matrix reaches 30-40%, and the dose of the rivastigmine required by 72-hour effective treatment can be met. The prepared patch has good cohesive force, can maintain the sticking time of at least 24 hours and has good mechanical property. Meanwhile, an EVA film with the vinyl acetate content of 19% is used as a controlled release film, so that the patch can perform in-vitro permeation at an approximately linear speed within 72 hours. Under the condition of rat skin, the carbalatin transdermal patch achieves the steady state permeation rate of more than 35 mu g/cm2h, the permeation curve is a linear equation and the in vitro permeation is performed at an approximate linear velocity with a correlation coefficient greater than 0.98.
The prepared rivastigmine drug delivery system can meet an approximately linear permeation curve within 72 hours by adopting an in-vitro permeation experiment on rat skin, and the 72-hour accumulated permeation quantity can reach 2531.20 +/-142.46 mu g/cm2Good linear relation of permeability curve, R2Reaches 0.993, and the steady state transmission rate is 37.17 mu g/cm2And/h, can meet the requirement of stable long-acting administration within 72 hours. In skin irritation experiments, no obvious red swelling and edema phenomena occur, and the transdermal drug delivery system is proved to have lower skin irritation.
Drawings
FIG. 1 is a release profile for examples 4-8.
FIG. 2 is an infrared spectrum of five prescriptions of matrix (PSA), drug (RVS), resin (E100), matrix + drug (PSA + RVS), matrix, resin and drug (PSA + E100+ RVS).
FIG. 3 is a rigid rheological profile of four formulations of matrix (PSA), matrix + drug (PSA + RVS), matrix + resin (PSA + E100), matrix, resin and drug (PSA + E100+ RVS).
FIG. 4 is a phase angle rheological profile of four prescriptions of matrix (PSA), matrix + drug (PSA + RVS), matrix + resin (PSA + E100), matrix, resin and drug (PSA + E100+ RVS).
FIG. 5 is a permeation curve for comparative example 1 and examples 5-7.
Detailed Description
Example 1: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive (trade name: acrylate pressure-sensitive adhesive) containing no group
87-4098)4.8g, weighing 1.4g of rivastigmine, and mixing for 2 hours until the mixture is uniform;
2) and (3) coating the drug-loaded pressure-sensitive adhesive on the anti-sticking layer to form a patch with the thickness of 50 mu m of the drug-loaded pressure-sensitive adhesive, drying for 15 minutes at 60 ℃, and compounding the release film.
Example 2: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive (trade name: hydroxy group-containing acrylate pressure-sensitive adhesive)
87-2287)5.0g, weighing 1.4g of rivastigmine, and mixing for 2 hours until the mixture is uniform;
2) and (3) coating the drug-loaded pressure-sensitive adhesive on the anti-sticking layer to form a patch with the thickness of 50 mu m of the drug-loaded pressure-sensitive adhesive, drying for 15 minutes at 60 ℃, and compounding the release film.
Example 3: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive containing carboxyl group (trade name
87-235A)4.7g, weighing 1.4g of rivastigmine, and mixing for 2 hours until the mixture is uniform;
2) and (3) coating the drug-loaded pressure-sensitive adhesive on the anti-sticking layer to form a patch with the thickness of 50 mu m of the drug-loaded pressure-sensitive adhesive, drying for 15 minutes at 60 ℃, and compounding the release film.
Example 4: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive containing carboxyl group (trade name
87-235A)6.5g, weighing 1.4g of rivastigmine, adding 0.2ml of 2.0mg/ml DL-alpha-tocopherol solution, and mixing for 2 hours until the mixture is uniform;
2) coating the drug-loaded pressure-sensitive adhesive on the anti-sticking layer to form a 120 mu m-thick patch of the drug-loaded pressure-sensitive adhesive, drying at 60 ℃ for 15 minutes to obtain a composite controlled release membrane CoTranTM 9712。
Example 5: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive containing carboxyl group (trade name
87-235A)5.1g, Ewing E1000.6g and rivastigmine 1.4g, adding 2.0mg/ml DL-alpha-tocopherol solution 4ml, mixing for 2 hours until uniform; standing for 1 hour to remove bubbles;
2) coating the drug-loaded pressure-sensitive adhesive on the anti-sticking layer to form a 120 mu m-thick patch of the drug-loaded pressure-sensitive adhesive, drying at 60 ℃ for 15 minutes to obtain a composite controlled release membrane CoTranTM 9712。
Example 6: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive containing carboxyl group (trade name
87-235A)4.5g, Ewing E1000.8g and rivastigmine 1.4g, 2ml of DL-alpha-tocopherol solution of 2.0mg/ml is added, and the mixture is mixed for 2 hours until the mixture is uniform; standing for 1 hour to remove bubbles;
2) coating the medicine-carrying pressure-sensitive adhesive on the anti-sticking layer to form a paster with the thickness of 110 mu m of the medicine-carrying pressure-sensitive adhesive, drying for 15 minutes at 60 ℃, and compounding a backing film ScotchpakTM 1109。
3) Adding 2.5g of Dow Corning 4202 organic silicon pressure-sensitive adhesive into 1ml of 1.5mg/ml DL-alpha-tocopherol solution and 0.15mg of dimeticone, and mixing for 2 hours until the mixture is uniform;
4) coating the organic silicon pressure-sensitive adhesive on the anti-sticking layer to form a paster with the thickness of 20 mu m, drying for 15 minutes at 60 ℃, and compounding a controlled release film CoTranTM 9712。
5) Combining the medicine-containing layer and the adhesive layer to obtain the rivastigmine transdermal patch.
Example 7: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive containing carboxyl group (trade name
87-235A)4.0g, EgyiE1001.0 g and rivastigmine 1.4g, adding 2.0mg/ml DL-alpha-tocopherol solution 1ml, mixing for 2 hours until uniform; standing for 1 hour to remove bubbles;
2) coating the medicine-carrying pressure-sensitive adhesive on the anti-sticking layer to form a paster with the thickness of 110 mu m of the medicine-carrying pressure-sensitive adhesive, drying for 15 minutes at 60 ℃, and compounding a backing film ScotchpakTM 1109。
3) Adding 2.5g of Dow Corning 4202 organic silicon pressure-sensitive adhesive into 1ml of 1.5mg/ml DL-alpha-tocopherol solution and 0.15mg of dimeticone, and mixing for 2 hours until the mixture is uniform;
4) coating the organic silicon pressure-sensitive adhesive on the anti-sticking layer to form a paster with the thickness of 15 mu m, drying for 15 minutes at 60 ℃, and compounding a controlled release film CoTranTM 9712。
5) Combining the medicine-containing layer and the adhesive layer to obtain the rivastigmine transdermal patch.
Example 8: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive containing carboxyl group (trade name
87-235A)5.0g, Ewing E1000.2g, rivastigmine 1.4g, carbitol 0.4g, 2ml of DL-alpha-tocopherol solution with 2.0mg/ml is added, and the mixture is mixed for 2 hours until the mixture is uniform; standing for 1 hour to remove bubbles;
2) coating the medicine-carrying pressure-sensitive adhesive on the anti-sticking layer to form a paster with the thickness of 110 mu m of the medicine-carrying pressure-sensitive adhesive, drying for 15 minutes at 60 ℃, and compounding a backing film ScotchpakTM 1109。
3) Adding 2.5g of Dow Corning 4202 organic silicon pressure-sensitive adhesive into 1ml of 1.5mg/ml DL-alpha-tocopherol solution and 0.15mg of dimeticone, and mixing for 2 hours until the mixture is uniform;
4) coating the organic silicon pressure-sensitive adhesive on the anti-sticking layer to form a paster with the thickness of 25 mu m, drying for 15 minutes at 60 ℃, and compounding a controlled release film CoTranTM 9712。
5) Combining the medicine-containing layer and the adhesive layer to obtain the rivastigmine transdermal patch.
Example 9
Example 9: preparation of rivastigmine transdermal patch
1) Weighing acrylate pressure-sensitive adhesive containing carboxyl group (trade name
87-235A)5.0g, Ewing E1000.4g, rivastigmine 1.4g, carbitol 0.2g, 2ml of DL-alpha-tocopherol solution with 2.0mg/ml is added, and the mixture is mixed for 2 hours until the mixture is uniform; the mixture was allowed to stand for 1 hour to remove air bubbles. Coating the medicine-carrying pressure-sensitive adhesive on the anti-sticking layer to form a paster with the thickness of 110 mu m of the medicine-carrying pressure-sensitive adhesive, drying for 15 minutes at 60 ℃, and compounding a backing film ScotchpakTM 1109。
2) Adding 2.5g of Dow Corning 4202 organic silicon pressure-sensitive adhesive into 1ml of 1.5mg/ml DL-alpha-tocopherol solution and 0.15mg of dimeticone, and mixing for 2 hours until the mixture is uniform;
3) coating the organic silicon pressure-sensitive adhesive on the anti-sticking layer to form a paster with the thickness of 25 mu m, drying for 15 minutes at 60 ℃, and compounding a controlled release film CoTranTM 9712。
4) Combining the medicine-containing layer and the adhesive layer to obtain the rivastigmine transdermal patch.
Comparative example 1: a commercially available rivastigmine transdermal patch, sold under the name EXELON, having a specification of 7792624 and a size of 9mg/5cm, was selected as a comparative example2
Example 10 Experimental evaluation of influencing factors (pressure-sensitive adhesive groups)
1. Instrument and reagent
The instrument comprises the following steps: shimadzu 2010A high performance liquid chromatograph.
Reagent testing: ethyl acetate (chromatographic grade, mai ruida), methanol (chromatographic grade, mai ruida), triethylamine (analytically pure), rivastigmine reference; rivastigmine transdermal patch (Dalianxiang homemade, lot numbers: 20191121 respectively)
2. Method and results
2.1 content determination Experimental method
Weighing the patch, placing into a volumetric flask, extracting the patch with the extract, performing ultrasonic treatment for half an hour, standing overnight, filtering the extracted patch solution with an organic phase filter membrane (0.5 ml before discarding), and performing chromatographic analysis on the filtered solution, wherein the chromatographic method is shown in 2.2.
2.2 Rivastigmine test sample analysis method
Using a silica gel column (5 μm 4.6X 250mm), mobile phase: ethyl acetate: methanol: triethylamine (90:10: 0.005); detection wavelength: 262 nm; flow rate: 1.0 mL/min; sample introduction amount: 20 mu L of the solution; column temperature: 30 ℃; extracting solution: ethyl acetate: methanol: calculated as percent diethylamine (30: 70: 0.4).
Table 1 examples 1-3 influencing factors experimental drug content
As can be seen from Table 1, only the carboxyl group pressure sensitive adhesive of the rivastigmine patches prepared in examples 1-3 had high stability. This indicates that: the rivastigmine has higher stability in acrylate pressure-sensitive adhesive containing carboxyl groups, and the matrix of the pressure-sensitive adhesive is selected from the pressure-sensitive adhesive containing carboxyl groups, which is favorable for the stability of medicaments.
Example 11 in vitro Release test
Instruments and reagent instruments: a horizontal osmotic diffusion system in vitro (KX-V/HDP); shimadzu 2010A high performance liquid chromatograph. Reagent testing: physiological saline; acetonitrile (chromatographic grade, mrida), purified water (vaaha), triethylamine (analytical grade), phosphoric acid (chromatographic grade); rivastigmine bitartrate control; rivastigmine transdermal patch (manufactured by Dalianxiang, with the respective lot numbers of 20201214 and 20210326); rivastigmine transdermal patch (product name EXELON sold in market, product number 7792624, specification of 9mg/5 cm)2)
2. Method and results
2.1 in vitro Release test method
The experimental device adopts a horizontal diffusion tank, the diffusion tank is formed by combining a left glass tank body and a right glass tank body, and the middle of the diffusion tank is connected by a clamp. When in use, the patch is placed in liquid once, the other side of the patch is fixed by an adhesive tape, and the left glass tube and the right glass tube are clamped by a clamp. The volume of the diffusion cell is 5ml, and the effective diffusion area is 0.785cm2. The patches of examples 4-5 and comparative example 1 were fixed, respectively; adding normal saline into the diffusion cell to the scale mark, removing bubbles, controlling the water bath temperature to be 32 +/-0.2 ℃, adding a stirrer, and stirring at constant temperature at the rotating speed of 600 r/min. 0.2mL of the solution was sampled from the diffusion cell by using a pipette at 1.2.4.7.11.24.32.48.72h after the start of the experiment, and the same volume and temperature of physiological saline (which was previously sonicated to remove air bubbles) were added.
The sample was centrifuged at 10000r/min for 10 minutes in a high-speed centrifuge, and then the supernatant was removed to prepare a test solution.
The rivastigmine bitartrate control was weighed precisely and placed in a 10ml volumetric flask, and a control solution with a concentration of 300 μ g/ml was prepared with a mobile phase (acetonitrile: water: triethylamine: 20: 80: 0.35-phosphoric acid to adjust PH to 3.5).
2.2 Rivastigmine test sample analysis method
Using a C18 column (4 × 250mm, 5 μm), mobile phase (acetonitrile: water: triethylamine: 20: 80: 0.35-phosphoric acid to PH 3.5); the detection wavelength was 210nm, the column temperature was 40 ℃, the flow rate was 1ml/min, 10. mu.L of sample was injected, and the cumulative release rate (%) was calculated. In vitro release curves were plotted on the Y-axis for cumulative release (%) and on the X-axis for release time (t), and the results are shown in figure 1, and the results for the cumulative release rate of 72h for the different patches are shown in table 2.
TABLE 2 cumulative release rates for different patches
| Patch preparation | 72h cumulative Release (%) |
| Example 4 | 63.46 |
| Example 5 | 76.61 |
| Example 6 | 84.37 |
| Example 7 | 77.67 |
| Example 8 | 84.56 |
In vitro release experiments show that the release amount of the resin added with E100 can be significantly increased in examples 5-8 compared with example 4, which indicates that the release behavior of the carboxyl pressure-sensitive adhesive can be improved by adding the resin, so that the research ensures the release amount of the drug while ensuring the stability of the drug.
With respect to the improvement of the release behavior of the patch, we conducted the following studies to explore the mechanism of the release improvement.
1) FTIR (Fourier infrared spectroscopy)
FTIR spectroscopy was used to study molecular interactions between RVS, E100 and PSA matrices to verify the mechanism of increased RVS release. As shown in FIG. 2, blank PSA, E100, RVS, PSA with RVS and PSA with RVS, E100 were studied. The IR spectrum showed that the PSA was 3240.84cm–1Has an O-H stretching vibration peak (COOH of PSA). With RVS or RVS-E100 in PSA, the wavenumber shift of COOH stretching is significantly weaker. This phenomenon can be explained by the complete ionisation of the COOH of the PSA, so that the H atoms leave the control of the carboxyl groups of the PSA, forming NH with the N atoms+。
For blank PSA, E100 and RVS, the C ═ O groups of the COOR group were each at 3446.23cm-13429.83 and 3430.81cm-1Showing overtone peaks. However, for PSA + RVS, the wavenumber red shifts to 3442.85cm–1Indicating that hydrogen bonding has occurred. For PSA with RVS and E100, the wavenumber is shifted to 3440.92cm–1Indicating that stronger hydrogen bonds are formed. In this system, the hydrogen donor can only be supplied by the COOH of the PSA. Compared to PSA + RVS, RVS + E100 has a reduced number of COOH in PSA, but shifts to lower wavenumbers. Thus, E100 has a higher ability to compete with RVS for H atoms, which means NH of E100+And the carbonyl group of PSA. The interaction between the RVS and the PSA is reduced, thereby increasing the diffusion rate and free volume of the RVS.
2) Differential Scanning Calorimetry (DSC)
The glass transition temperature (Tg) of the pressure sensitive adhesive was measured by DSC to reflect the segmental motion of the polymer. All factors that affect the flexibility of the polymer chains change the Tg. In general, a higher Tg value means that larger hydrogen bonds will be formed in the system, thereby reducing the mobility of the PSA. As shown in Table 3, the Tg values for the blank PSA, PSA with RVS and E100 were-31.35 deg.C, -40.25 deg.C and-37.81 deg.C, respectively. The results show that E100 reduces the interaction between RVS and PSA, thereby freeing more RVS molecules to move in the space obtained by E100 swelling.
TABLE 3 glass transition temperatures (Tg) of the different substrates
| Species of | Tg(℃) |
| Blank PSA | -31.35 |
| PSA+RVS | -40.25 |
| PSA+E100+RVS | -27.81 |
3) Rheology study
Two parameters were calculated separately to evaluate the rheological properties of the adhesive. The fluidity of the adhesive was evaluated by the phase shift angle (. delta.). The higher the value of δ, the higher the fluidity of the adhesive. The high fluidity of the binder facilitates the release of small molecules from the binder, and the complex viscosity η is a direct measure of the hardness of the binder, which may hinder the drug release behaviour. Both of these indicators may imply molecular interactions in complex systems.
By comparing the low frequency regions in figure 3, the flowability of the adhesive in PSA with RVS and E100 was superior to the PSA + RVS and blank PSA group, illustrating the improved release behavior of the RVS and the interaction between the PSA and E100. Meanwhile, as shown in fig. 4, the hardness of the adhesive in PSA + E100 is much higher than the other three groups, which means that stronger molecular interactions such as hydrogen bonds are formed between PSA and E100.
Table 4 rheological parameters in different matrices
| Species of | G’ | G” | δ | η* |
| Blank PSA | 2.45 | 1.05 | 23.11 | 4.24 |
| PSA+E100 | 4.78 | 2.87 | 30.99 | 8.87 |
| PSA+E100+RVS | 0.93 | 0.73 | 38.22 | 1.87 |
| PSA+RVS | 0.60 | 0.49 | 39.01 | 1.23 |
Example 12 in vitro transdermal Permeability test
Instruments and reagent instruments: horizontal type in vitro permeation diffusion system (KX)-V/HDP); shimadzu 2010A high performance liquid chromatograph. Reagent testing: physiological saline; acetonitrile (chromatographic grade, mrida), purified water (vaaha), triethylamine (analytical grade), phosphoric acid (chromatographic grade); rivastigmine bitartrate control; rivastigmine transdermal patch (manufactured by Dalianxiang, with the respective batch numbers: 20210326, 20210416); rivastigmine transdermal patch (product name EXELON sold in market, product number 7792624, specification of 9mg/5 cm)2)
2. Method and results
The only difference from the in vitro release test is that the stratum corneum of the skin is facing the patch and the other side is exposed to normal saline. And the cumulative permeability (%) was calculated. In vitro permeation curves were plotted with the Y-axis as the cumulative permeation (%) and the X-axis as the permeation time (t), and the results are shown in fig. 5.
QtThe cumulative permeation at time t (μ g/cm)2)；M0Is the initial drug content; rtIs the cumulative transmittance; v is the volume of receiving fluid (mL); cnConcentration in the nth sample (. mu.g/mL); vnIs the sampling volume;
TABLE 5 cumulative Permeability of different patches
| Patch preparation | 72h cumulative Permeability (%) |
| Example 5 | 60.84 |
| Example 6 | 50.28 |
| Example 7 | 58.28 |
| Comparative example 1 | 60.08(24h) |
As can be seen from FIG. 5, the rivastigmine patch prepared by the in vitro permeation test on rat skin can satisfy the approximately linear permeation curve within 72 hours, and the 72-hour accumulated permeation amount can reach 2531.20 + -142.46 μ g/cm2Good linear relation of permeability curve, R2Reaches 0.993, and the steady state transmission rate is 37.17 mu g/cm2And/h, can meet the requirement of stable long-acting administration within 72 hours.
The rivastigmine patches prepared in examples 5-7 all had good in vitro permeation properties, while the rivastigmine patches prepared in example 6 had a curve that was able to permeate at an approximately linear rate, demonstrating that rivastigmine patches prepared using controlled release membrane 9712 and adhesive layer 4202 had long-lasting, stable release and permeation properties that were able to deliver the drug stably over 72 hours.
As can be seen from Table 5, the cumulative permeability at 24h in comparative example 1 is comparable to the cumulative permeability at 72h in examples 5 and 7, which demonstrates that the examples not only maintain the linear permeation rate, but also ensure the drug utilization rate to be consistent with that of the comparative examples.
Example 13 mechanical evaluation
Permanent adhesion experiment: the transdermal patches of examples 6-8 and comparative examples were attached to a clean stainless steel plate placed vertically (the stainless steel plate was wiped with absolute ethanol before use), rolled on each patch 3 times with a 2kg roller, then left at room temperature for 20 minutes, and a 1kg weight was placed under the patch with the pulling direction parallel to the gravity direction, and the time required for the patch to completely fall off was recorded, and the patches were directly removed after more than 24 hours, and the results are shown in table 6.
TABLE 6 mechanical evaluation of Patches
| Patch preparation | Permanent adhesion |
| Comparative example 1 | 45 seconds |
| Example 6 | Greater than 24 hours |
| Example 7 | Greater than 24 hours |
| Example 8 | Greater than 24 hours |
As can be seen from Table 6: the rivastigmine patches prepared in examples 6-8 all had better mechanical properties (the short time to stick in comparative example 1 may be due to the patch area failing to meet pharmacopoeia test standards). The rivastigmine patch prepared by the method has better mechanical property and can meet the requirement of long-time administration.
Example 14 skin irritation test
Four Japanese Long-ear rabbits were selected and administered for 72 hours in example 1 and 24 hours in comparative example 1 by the in vivo and self-control method, and the degree of skin redness and edema was observed 30 minutes, 24, 48, and 72 hours after the removal of the drug.
The dyeing picture proves that the stratum corneum at the outermost layer has no obvious damage, which indicates that the safety of the patch reaches the standard. The phenomena of edema and redness are not obvious after the administration of the active ingredients in the embodiment 6 and the comparative example 1, and the prepared rivastigmine long-acting transdermal patch can meet the skin irritation requirement within 72 hours and has good skin compatibility and safety.
*: the pressure sensitive adhesive used in this application is a liquid, and the weight of the solvent is subtracted from the weight of the remaining solids, and the solvent accounts for 60% of the total weight.
**: in the embodiment, the pressure sensitive adhesive layer containing the medicine also contains 10 percent of penetration enhancer carbitol.
The production methods of examples 15 to 17 were carried out by referring to the production method of example 7, and only the selection of the amounts and kinds shown in the above table was carried out instead, and the other conditions were not changed.
The objective of this patent is to develop a long-acting transdermal drug delivery system of rivastigmine, which should meet all the requirements of table 7, and at the same time, the patch should achieve approximately linear permeation rate within 72h, and therefore should meet the following table requirements. I.e., the first steady state permeation rate is greater than 35, the second permeation curve is a linear equation, and the correlation coefficient of the third linear equation must be greater than 0.98.
Judgment basis of long-acting rivastigmine transdermal drug delivery system
Claims (6)
1. A long acting transdermal patch of rivastigmine comprising layers arranged in the following order: a back lining layer, a medicine-containing pressure-sensitive adhesive layer, a controlled release film, an adhesive layer and a protective layer;
the method is characterized in that: the back lining layer is a polyester film;
the pressure-sensitive adhesive in the medicine-containing pressure-sensitive adhesive layer is acrylic pressure-sensitive adhesive containing carboxyl groups; in the medicine-containing pressure-sensitive adhesive layer, the weight of the acrylic acid pressure-sensitive adhesive is 30-49.9%; 30-40% by weight of rivastigmine; 10-30% by weight of polyacrylic resin; 0.01 to 0.2 percent by weight of DL-alpha-tocopherol;
the controlled release film is an EVA film with the mass fraction of vinyl acetate monomer of 19%;
the adhesive layer contains 99.80-99.89% of silicone pressure sensitive adhesive, 0.01-0.1% of dimeticone and 0.1% of DL-alpha-tocopherol;
the polyester film is one of 3M Scotchpak 1109,9723,9736 and 9738;
the acrylic pressure-sensitive adhesive contains free carboxyl, and is selected from one or more of DURO-TAK 87-2852, DURO-TAK 87-2677 and DURO-TAK 87-235A; the polyacrylic resin is selected from Eudragit E100 and/or Eudragit EPO;
the membrane for controlling the release of rivastigmine is CoTran 9712;
the organic silicon pressure-sensitive adhesive is selected from BIO-PSA of DOW CORNINGTM7-4202 and 7-4302.
2. The long-acting transdermal patch of rivastigmine according to claim 1, wherein:
4.0-6.5g of acrylic ester pressure sensitive adhesive containing carboxyl groups in the medicine-containing pressure sensitive adhesive layer, 1.3-1.5g of rivastigmine, 0.2-4 mL of 2mg/mL DL-alpha-tocopherol solution and 0.2-1.0g of polyacrylic resin.
3. The long-acting transdermal patch of rivastigmine according to claim 1 or 2, wherein: the long-acting transdermal patch is a patch that is applied to the skin for at least 72 hours and exhibits steady-state skin penetration.
4. The long-acting transdermal patch of rivastigmine according to claim 1 or 2, wherein: 0-20% of penetration enhancer is added into the medicine-containing pressure-sensitive adhesive layer, and the penetration enhancer is selected from azone, carbitol or oleic acid.
5. The long-acting transdermal patch of rivastigmine according to claim 1, wherein: the rivastigmine content of the patch is 23-30mg, and the thickness of the medicine-containing pressure-sensitive adhesive layer is 90-120 μm.
6. The long-acting transdermal patch of rivastigmine according to claim 1, wherein: the patch has a size of 5-20cm2。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110985399.3A CN113616625B (en) | 2021-08-26 | 2021-08-26 | Long-acting transdermal patch of rivastigmine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110985399.3A CN113616625B (en) | 2021-08-26 | 2021-08-26 | Long-acting transdermal patch of rivastigmine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113616625A true CN113616625A (en) | 2021-11-09 |
| CN113616625B CN113616625B (en) | 2023-05-30 |
Family
ID=78387809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110985399.3A Active CN113616625B (en) | 2021-08-26 | 2021-08-26 | Long-acting transdermal patch of rivastigmine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113616625B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114306288A (en) * | 2022-01-16 | 2022-04-12 | 沈阳药科大学 | Rivastigmine long-acting percutaneous absorption patch and preparation method thereof |
| CN117064866A (en) * | 2023-07-10 | 2023-11-17 | 北京丰科睿泰医药科技有限公司 | Burisperidone long-acting transdermal patch and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101312717A (en) * | 2005-12-01 | 2008-11-26 | 诺瓦提斯公司 | Transdermal therapeutic system |
| CN103269698A (en) * | 2010-12-14 | 2013-08-28 | 阿西诺股份公司 | Transdermal therapeutic system for administering an active substance |
| US20140271866A1 (en) * | 2013-03-15 | 2014-09-18 | Nal Pharmaceuticals, Ltd. | Transdermal drug delivery system containing rivastigmine |
| EP2821070A1 (en) * | 2012-02-28 | 2015-01-07 | Nichiban Co. Ltd. | Adhesive skin patch |
-
2021
- 2021-08-26 CN CN202110985399.3A patent/CN113616625B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101312717A (en) * | 2005-12-01 | 2008-11-26 | 诺瓦提斯公司 | Transdermal therapeutic system |
| CN103269698A (en) * | 2010-12-14 | 2013-08-28 | 阿西诺股份公司 | Transdermal therapeutic system for administering an active substance |
| EP2821070A1 (en) * | 2012-02-28 | 2015-01-07 | Nichiban Co. Ltd. | Adhesive skin patch |
| US20140271866A1 (en) * | 2013-03-15 | 2014-09-18 | Nal Pharmaceuticals, Ltd. | Transdermal drug delivery system containing rivastigmine |
Non-Patent Citations (1)
| Title |
|---|
| 郭玉莹: ""卡巴拉汀透皮贴片的处方及工艺研究"", 《中国优秀硕士学位论文全文数据库（电子期刊） 医药卫生科技辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114306288A (en) * | 2022-01-16 | 2022-04-12 | 沈阳药科大学 | Rivastigmine long-acting percutaneous absorption patch and preparation method thereof |
| CN117064866A (en) * | 2023-07-10 | 2023-11-17 | 北京丰科睿泰医药科技有限公司 | Burisperidone long-acting transdermal patch and preparation method thereof |
| CN117064866B (en) * | 2023-07-10 | 2024-04-19 | 北京丰科睿泰医药科技有限公司 | Burisperidone long-acting transdermal patch and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113616625B (en) | 2023-05-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2153828B1 (en) | Composition for the Transdermal Delivery of Fentanyl | |
| CN113616625B (en) | Long-acting transdermal patch of rivastigmine | |
| TWI411452B (en) | Transdermal therapeutic system for administering the active ingredient buprenorphine | |
| EP3253840B1 (en) | Pressure-sensitive adhesives for transdermal drug delivery | |
| KR101737960B1 (en) | Pharmaceutical composition for external use | |
| Liu et al. | Drug in adhesive patch of palonosetron: Effect of pressure sensitive adhesive on drug skin permeation and in vitro-in vivo correlation | |
| AU2002215315A1 (en) | Composition for the transdermal delivery of fentanyl | |
| EP3644973B1 (en) | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer | |
| JP5936544B2 (en) | Stable rasagiline composition | |
| US9585862B2 (en) | Patch containing rivastigmine | |
| Kim et al. | Effect of plasticizers on drug-in-adhesive patches containing 5-fluorouracil | |
| UA81803C2 (en) | Highly pure bases of 3,3-diphenyl propylamine monoesters | |
| US10406116B2 (en) | Pressure-sensitive adhesives for transdermal drug delivery | |
| CN107929267A (en) | Transdermal plaster of rivastigmine and preparation method thereof | |
| CN108685879B (en) | Rivastigmine transdermal patch and preparation method thereof | |
| US20140370077A1 (en) | Transdermal drug delivery system containing fentanyl | |
| TWI720366B (en) | Transdermal patch | |
| CN111195242B (en) | Percutaneous absorption patch | |
| CN101120933B (en) | Transdermal paster containing bulleyaconitine A and its preparation method | |
| Mandli et al. | Design, Development, and Delivery of Rasagiline mesylate from Monolithic Drug in Adhesive Matrix Patches | |
| WO2020116587A1 (en) | Polymer micelle carrier composition and medicine-containing polymer micelle composition | |
| Pethani et al. | Formulation Designing Factors For Development Of Repaglinide Transdermal Therapeutic System | |
| CN116509820A (en) | Rivastigmine transdermal patch | |
| CN115778923A (en) | Use of polymethacryloxyethyltrimethylammonium chloride as adhesive for gel emplastrum paste layer | |
| CN111867570A (en) | Transdermal therapeutic system comprising nicotine and silicone acrylic hybrid polymers |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |