CN113116864A - Multilayer film containing medicine and method for forming the same - Google Patents

Multilayer film containing medicine and method for forming the same Download PDF

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CN113116864A
CN113116864A CN202010001917.9A CN202010001917A CN113116864A CN 113116864 A CN113116864 A CN 113116864A CN 202010001917 A CN202010001917 A CN 202010001917A CN 113116864 A CN113116864 A CN 113116864A
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polylactic acid
drug
polyethylene glycol
multilayer film
layer
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沈欣欣
王羽淇
林立信
杨明嘉
黄秀华
苏良晟
赵樱雪
黄靖恩
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Industrial Technology Research Institute ITRI
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

A drug-containing multilayer film is provided. The drug-containing multilayer film comprises: a drug-containing layer; and an anti-sticking layer on a surface of the drug-containing layer. The drug-containing layer is composed of a first composition, the first composition comprises a first polymer material and a drug, the first polymer material comprises at least one selected from the group consisting of: polylactic acid (PLA) and polyethylene glycol (PEG), and the weight ratio of the first polymer material to the drug is about 1: 0.01-0.3. The anti-sticking layer is composed of a second composition, the second composition includes a second polymer material, the second polymer material includes at least one selected from the group consisting of: polylactic acid and polyethylene glycol.

Description

Multilayer film containing medicine and method for forming the same
Technical Field
The present disclosure relates to medical films, and more particularly to a drug-containing multilayer film and a method for forming the same.
Background
According to the research, the adhesion after the operation can cause various complications, such as small intestine blockage, chronic pelvic pain, infertility and the like, so that the adhesion after the operation is avoided, the discomfort possibly caused in the follow-up process of a patient can be reduced, the risk that the patient needs to be subjected to the operation again due to the adhesion problem can be reduced, and the expenditure of medical resources can be saved.
In addition to the adhesion caused by the operation, the wound healing period after the operation may also cause pain or infection, so that the use of drugs such as pain killer and antibiotics is required to relieve the discomfort of the patient.
At present, four ways of postoperative analgesia mainly comprise intramuscular injection, intravenous injection, patient self-control analgesia and continuous epidural analgesia. Both intramuscular and intravenous injections require repeated administration of the drug over several hours to maintain the analgesic effect, but can also cause side effects.
Thus, there is a need for medical devices that reduce or avoid both sticking and discomfort associated with surgery.
Disclosure of Invention
The present disclosure provides a medicated multilayer film, comprising: a drug-containing layer; and an anti-sticking layer on a surface of the drug-containing layer. The drug-containing layer is composed of a first composition, the first composition comprises a first polymer material and a drug, the first polymer material comprises at least one selected from the group consisting of: polylactic acid (PLA) and polyethylene glycol (PEG), and the weight ratio of the first polymer material to the drug is about 1: 0.01-0.3. The anti-sticking layer is composed of a second composition, the second composition includes a second polymer material, the second polymer material includes at least one selected from the group consisting of: polylactic acid and polyethylene glycol.
The present disclosure also provides a method for forming a drug-containing multilayer film, which includes the following steps (a) or (b). Mode (a), comprising: (i) drying the first solution to form a film so as to form a medicine-containing layer; and (ii) drying a second solution to form a film on a surface of the drug-containing layer to form an anti-sticking layer. Mode (b), comprising: (i') drying the second solution to form a film to form an anti-sticking layer; and (ii') drying a first solution to form a film on the anti-sticking layer to form a drug-containing layer. The solute of the first solution comprises a first polymer material and a drug, the first polymer material comprising at least one selected from the group consisting of: polylactic acid and polyethylene glycol, wherein the content of the first polymer material in the first solution is about 5-30 wt%, and the weight ratio of the first polymer material to the drug is about 1: 0.01-0.3. The solute of the second solution comprises a second polymer material comprising at least one selected from the group consisting of: polylactic acid and polyethylene glycol, and the content of the second polymer material in the second solution is about 5-30 wt%.
In order to make the aforementioned and other objects, features and advantages of the present invention comprehensible, preferred embodiments accompanied with figures are described in detail as follows:
drawings
FIG. 1 shows an embodiment of a method for forming a multi-layer film containing a drug according to the present disclosure.
FIG. 2 shows another embodiment of the disclosed method for forming a multi-layer film containing a drug.
FIG. 3 shows, in one embodiment, a method for forming a drug-containing layer of a multi-layer thin film containing a drug according to the present disclosure.
FIG. 4 shows yet another embodiment of the disclosed method for forming a drug-containing multilayer film.
FIG. 5 shows yet another embodiment of the disclosed method for forming a drug-containing multilayer film.
FIG. 6A is a photograph showing a cell experiment in an anti-sticking test of an anti-sticking film.
FIG. 6B shows the results of cell survival analysis of cell experiments in the anti-adhesion test of anti-adhesion films.
FIG. 7 shows the operation of an animal experiment in an anti-sticking test of an anti-sticking film.
FIG. 8A is a photograph showing the operation area of each group of rats in an animal experiment in an anti-sticking test of an anti-sticking film.
FIG. 8B shows the percentage of the number of lightly stained and moderately or heavily stained rats in each group in the anti-staining test of the anti-staining film.
FIG. 9 shows a photograph of the disclosed drug-containing multilayer film RM.
FIG. 10 shows the results of immediate release testing of the drug-containing multilayer films M-01, M-02, M-03, M-04, M-05 and M-06 of the present disclosure.
FIG. 11 shows the results of immediate release testing of the drug-containing multilayer film M-02 (without a protective layer) and the drug-containing multilayer films M-07, M-08, M-09, and M-10 (with a protective layer) according to the present disclosure.
FIG. 12 shows the release test results of the drug-containing multilayer film M-05 (without a protective layer) and the drug-containing multilayer films M-11 and M-12 according to the present disclosure.
FIG. 13 shows the results of the release test for the drug-containing multilayer film M-11 (without microstructure in the drug-containing layer) and the drug-containing multilayer films MS-1, MS-2 and MS-3 according to the present disclosure.
FIG. 14 shows the results of SEM analysis of the drug-containing multilayer films MS-1, MS-2 and MS-3 according to the present disclosure.
FIG. 15 shows the results of the release test for the drug-containing multilayer films MS-1, MS-2, MS-1-B and MS-2-B.
FIG. 16 shows the results of scanning electron microscope analysis of the drug-containing multilayer films MS-1-B and MS-2-B.
Description of the symbols
100、100’、200、200’
Figure BDA0002353796750000031
The disclosed drug-containing multilayer film;
101、101’
Figure BDA0002353796750000032
a drug-containing layer;
103、103’
Figure BDA0002353796750000033
an anti-sticking layer;
105、105’
Figure BDA0002353796750000034
a protective layer;
S1、S1’、S2、S2’
Figure BDA0002353796750000035
the surface of the medicine-containing layer 101, 101';
D
Figure BDA0002353796750000036
a drug;
MS
Figure BDA0002353796750000037
a microstructure of the drug-containing layer 101';
P
Figure BDA0002353796750000038
a flat plate;
R
Figure BDA0002353796750000039
a groove of the plate.
Detailed description of the preferred embodiments
The present disclosure provides a drug-containing multilayer film. The disclosed medicated multilayer film is a biodegradable non-fibrous film that can be well attached to surgical or diffuse wounds without being secured by sutures or other means and prevents leakage of interstitial fluid. In addition, the disclosed multi-layer film containing drug has anti-sticking effect, which can avoid the occurrence of undesired tissue sticking, and at the same time, can release the required drug to the wound or tissue area to which the film is attached, so as to achieve the required medical effect.
The medicated multilayer film of the present disclosure may include, but is not limited to, a medicated layer and an anti-adhesive layer, the anti-adhesive layer being disposed on a surface of the medicated layer.
The drug-containing layer may be comprised of a first composition. The first composition may include, but is not limited to, a first polymer material and a drug. In one embodiment, the weight ratio of the first polymer material to the drug can be about 1:0.01-0.3, such as 1:0.05-0.25, about 1:0.1, about 1:0.15, about 1:0.2, and the like, but is not limited thereto.
Examples of the first polymer material include, but are not limited to, polylactic acid (PLA), polyethylene glycol (PEG), and the like, or any combination thereof.
The polylactic acid in the above examples of the first polymer material may include polylactic acids having different viscosities and any combination thereof. For example, the polylactic acid in the above-mentioned example of the first polymer material may include a first polylactic acid, a second polylactic acid or a combination thereof, wherein the first polylactic acid and the second polylactic acid may have different viscosities. The viscosity of the first polylactic acid may be, but is not limited to, about 0.05 to 1dl/g, for example, about 0.4 to 0.6dl/g, etc., and the viscosity of the second polylactic acid may be, but is not limited to, about 1.1 to 3.0dl/g, for example, about 1.6 to 2.4 dl/g.
Further, the polyethylene glycol in the above examples of the first polymer material may include polyethylene glycols of different average molecular weights and any combination thereof. For example, the polyethylene glycol in the above-mentioned first polymer material example can include a first polyethylene glycol, a second polyethylene glycol or a combination thereof, wherein the first polyethylene glycol and the second polyethylene glycol can have different average molecular weights. The average molecular weight of the first polyethylene glycol can be, but is not limited to, about 100-.
In an embodiment, in the drug-containing layer, the first polymer material includes polylactic acid. In this embodiment, the polylactic acid may be the first polylactic acid, the second polylactic acid, or a combination thereof.
In another embodiment, in the drug-containing layer, the first polymer material may include both polylactic acid and polyethylene glycol. In this embodiment, the polylactic acid may be the first polylactic acid or the second polylactic acid, and the polyethylene glycol may be the first polyethylene glycol, the second polyethylene glycol, or a combination thereof. In this embodiment, the weight ratio of polylactic acid to polyethylene glycol in the drug-containing layer may be about 1:0.05-1, such as, but not limited to, about 1:0.1, about 1:0.2, about 1:0.25, about 1:0.3, about 1:0.4, about 1:0.43, about 1:0.5, about 1:0.75, and the like.
In a specific embodiment, the first polymer material may include both polylactic acid and polyethylene glycol, and the polylactic acid may be the first polylactic acid or the second polylactic acid, and the polyethylene glycol may be the first polyethylene glycol or the second polyethylene glycol.
In another specific embodiment, the first polymer material may include both polylactic acid and polyethylene glycol, and the polylactic acid may be the first polylactic acid or the second polylactic acid, and the polyethylene glycol may be a combination of the first polyethylene glycol and the second polyethylene glycol. In this particular embodiment, the weight ratio of the first polyethylene glycol to the second polyethylene glycol may be about 1:0.05-20, such as 1:0.1, 1:0.2, 1:0.5, 1:1, 1:5, 1:10, 1:15, etc., but is not limited thereto.
Further, the drug in the drug-containing layer of the drug-containing multilayer film of the present disclosure is not particularly limited, and may be selected as desired as long as it can be released through the drug-containing multilayer film of the present disclosure without adversely affecting other components in the drug-containing layer, such as formation of the drug-containing layer or inactivation of the drug.
Examples of the drug in the drug-containing layer may include, but are not limited to, an analgesic, an anti-inflammatory analgesic, an antibiotic, and the like. Analgesics may include, but are not limited to, lidocaine hydrochloride, morphine hydrochloride, phentany, and the like. Anti-inflammatory analgesics may include, but are not limited to, nonsteroidal anti-inflammatory analgesics (NSAIDs), such as ibuprofen (ibuprofen), naproxen (naproxen), aspirin (aspirin), fenbufen (fenbufen), indomethacin (indomethacin), diclofenac sodium (diclofenac sodium), and the like. Antibiotics may include, but are not limited to, vancomycin (vancomycin), rifampin (rifampin), and the like.
In a specific embodiment, in the medicated multilayer film of the present disclosure, the first polymeric material in the medicated layer is polylactic acid, which may have a viscosity of about 0.05-1dl/g, and the drug in the medicated layer may include an analgesic, an anti-inflammatory analgesic, or a combination thereof. Also, in this particular embodiment, the disclosed drug-containing multilayer film has the effect of releasing the drug immediately.
In another specific embodiment, in the medicated multilayer film of the present disclosure, the first polymeric material in the medicated layer is polylactic acid, which is a second polylactic acid having a viscosity of about 1.1-3.0dl/g, and the drug in the medicated layer may include an analgesic, an antibiotic, or a combination thereof. Also, in this particular embodiment, the disclosed drug-containing multilayer film has the effect of sustained release of the drug.
In another specific embodiment, in the multi-layer film containing drug of the present disclosure, the first polymer material in the drug-containing layer is a combination of polylactic acid and polyethylene glycol, the polylactic acid is the first polylactic acid with the viscosity of about 0.05-1dl/g, the polyethylene glycol is the first polyethylene glycol with the average molecular weight of about 100-. Also, in this particular embodiment, the disclosed drug-containing multilayer film has the effect of releasing the drug immediately.
In another specific embodiment, in the multi-layer film containing drug of the present disclosure, the first polymer material in the drug-containing layer is a combination of polylactic acid and polyethylene glycol, the polylactic acid is the second polylactic acid with the viscosity of about 1.1-3.0dl/g, the polyethylene glycol is the first polyethylene glycol with the average molecular weight of about 100-1,000 or the second polyethylene glycol with the average molecular weight of about 4,000-10,000, and the drug in the drug-containing layer may include the above-mentioned analgesic, antibiotic or their combination. Also, in this particular embodiment, the disclosed drug-containing multilayer film has the effect of sustained release of the drug.
In another specific embodiment, in the multi-layer film containing drug of the present disclosure, the first polymer material in the drug-containing layer is a combination of polylactic acid and polyethylene glycol, the polylactic acid is the first polylactic acid with viscosity of about 0.05-1dl/g, and the polyethylene glycol is a combination of the first polyethylene glycol with average molecular weight of about 100-. The drug in the drug-containing layer may include an analgesic, an anti-inflammatory analgesic, or a combination thereof. Also, in this particular embodiment, the disclosed drug-containing multilayer film has the effect of releasing the drug immediately.
In another specific embodiment, in the multi-layer film containing drug of the present disclosure, the first polymer material in the drug-containing layer is a combination of polylactic acid and polyethylene glycol, the polylactic acid is the second polylactic acid with the viscosity of about 1.1-3.0dl/g, and the polyethylene glycol is a combination of the first polyethylene glycol with the average molecular weight of about 100-1,000 and the second polyethylene glycol with the average molecular weight of about 4,000-10,000, and the weight ratio of the first polyethylene glycol to the second polyethylene glycol is about 1: 0.01-20. The drug in the drug-containing layer may include the above analgesics, antibiotics, or combinations thereof. Also, in this particular embodiment, the disclosed drug-containing multilayer film has the effect of sustained release of the drug.
In addition, in one embodiment, the drug-containing layer of the disclosed drug-containing multilayer film may have at least one microstructure protruding from the other surface thereof, where the other surface of the drug-containing layer is located on the opposite side of the anti-sticking layer.
The microstructure can have an upper surface. The shape of the upper surface can be, but is not limited to, a curved surface, a flat plate, etc. The microstructures described herein do not include pyramidal or acicular shapes.
Also, the ratio of the height of the microstructures to the width of the base may be about 1:2-4, such as 1:1, 1:1.5, 1:2, etc., but is not limited thereto.
In one embodiment, the drug-containing layer has a plurality of microstructures. In this embodiment, the center-to-center distance between two adjacent microstructures in the plurality of microstructures may be about 50-2,000 μm, such as, but not limited to, about 75 μm, about 100 μm, about 150 μm, about 200 μm, about 220 μm, about 250 μm, about 300 μm, about 350 μm, about 400 μm, about 500 μm, about 1,000 μm, about 1,500 μm, and the like.
In the embodiment where the drug-containing layer has a plurality of microstructures, the density of the microstructures on the drug-containing layer can be about 0.1-100 microstructures/cm2E.g., about 1 to about 30 microstructures/cm2About 0.01 microstructure/cm2About 0.25 microstructure/cm2About 0.5 microstructure/cm2About 1 microstructure/cm2About 2 microstructures/cm2About 3 microstructures/cm2About 4 microstructures/cm2About 5 microstructures/cm2About 9 microstructures/cm2About 10 microstructures/cm2About 13 microstructures/cm2About 15 microstructures/cm2About 16 microstructures/cm2About 20 microstructures/cm2About 25 microstructures/cm2About 29 microstructures/cm2About 30 microstructures/cm2About 35 microstructures/cm2About 36 microstructures/cm2About 49 microstructures/cm2About 50 microstructures/cm2About 60 microstructures/cm2About 64 microstructures/cm2About 65 microstructures/cm2About 70 microstructure/cm2About 75 microstructures/cm2About 80 microstructures/cm2About 81 microstructures/cm2About 90 microstructures/cm2About 100 microstructures/cm2But is not limited thereto. The drug release efficiency is increased by increasing the density of the microstructure.
In addition, in the embodiment where the drug-containing layer has a plurality of microstructures, the shape and/or the manner of the plurality of microstructures of the drug-containing layer are not particularly limited, and can be adjusted as required. For example, the plurality of microstructures may be arranged in a shape including but not limited to a rectangle, a circle, a triangle, and an irregular shape, or the plurality of microstructures may be uniformly or non-uniformly dispersed on the drug-containing layer. In a specific embodiment, the plurality of microstructures of the drug-containing layer are arranged in a matrix.
The thickness of the drug-containing layer of the disclosed drug-containing multilayer film may be about 5-55 μm, such as about 20-25 μm, but is not limited thereto.
The anti-sticking layer of the multi-layer film containing drug of the present disclosure can be formed by a second composition. The second composition may include, but is not limited to, a second polymeric material.
Examples of the second polymer material include, but are not limited to, polylactic acid, polyethylene glycol, and the like, or any combination thereof.
The viscosity of the polylactic acid in the above-mentioned example of the second polymer material may be about 1.1 to 3.0dl/g, such as about 1.6 to 2.4dl/g, but is not limited thereto.
Further, the polyethylene glycol in the above examples of the second polymer material may include polyethylene glycols having various average molecular weights and any combination thereof. For example, the polyethylene glycol in the above-mentioned second polymer material may include a third polyethylene glycol, a fourth polyethylene glycol or a combination thereof, wherein the third polyethylene glycol and the fourth polyethylene glycol may have different average molecular weights. The average molecular weight of the third polyethylene glycol can be, but is not limited to, about 100-.
In one embodiment, in the anti-sticking layer, the second polymer material may include polylactic acid, and the viscosity of the polylactic acid may be about 1.1 to 3.0dl/g, but is not limited thereto.
In another embodiment, in the anti-sticking layer, the second polymer material may include both polylactic acid and polyethylene glycol. In this embodiment, the viscosity of the polylactic acid may be about 1.1 to 3.0dl/g, and the polyethylene glycol may be the third polyethylene glycol described above, the fourth polyethylene glycol described above, or a combination thereof. In this embodiment, the weight ratio of the polylactic acid to the polyethylene glycol in the anti-sticking layer may be about 1:0.01-0.5, for example, about 1:0.05, about 1:0.1, about 1:0.11, about 1:0.2, about 1:0.24, about 1:0.25, about 1:0.3, about 1:0.4, about 1:0.45, etc., but is not limited thereto.
Also, in a specific embodiment, the second polymer material may include both polylactic acid and polyethylene glycol, the viscosity of the polylactic acid may be about 1.1 to 3.0dl/g, and the polyethylene glycol may be the third polyethylene glycol or the fourth polyethylene glycol.
In another specific embodiment, the second polymeric material may include both polylactic acid and polyethylene glycol, the viscosity of polylactic acid may be about 1.1-3.0dl/g, and the polyethylene glycol may be a combination of the third polyethylene glycol and the fourth polyethylene glycol. In this particular embodiment, the weight ratio of the third polyethylene glycol to the fourth polyethylene glycol may be about 1:0.2-5, such as 1:0.25, 1:0.4, 1:0.5, 1:1, 1:2, 1:3, 1:4, etc., but is not limited thereto.
The anti-sticking layer of the disclosed medicated multilayer film may have a thickness of about 10-60 μm, such as about 25-30 μm, but is not limited thereto.
Furthermore, in an embodiment of the present disclosure, in addition to the above-mentioned drug-containing layer and the anti-sticking layer, the drug-containing multilayer film of the present disclosure may further include a protective layer on another surface of the above-mentioned drug-containing layer, wherein the drug-containing layer is located between the anti-sticking layer and the protective layer.
The protective layer may be formed of a third composition. The third composition may include a third polymeric material, but is not limited thereto.
Examples of the third polymeric material may include, but are not limited to, polylactic acid, polyethylene glycol, and the like, or any combination thereof.
The polylactic acid in the third polymer material may include polylactic acid with different viscosity and any combination thereof. For example, the polylactic acid in the third polymer material example may include a third polylactic acid, a fourth polylactic acid or a combination thereof, wherein the third polylactic acid and the fourth polylactic acid may have different viscosities. The viscosity of the third polylactic acid may be, but is not limited to, about 0.05 to 1dl/g, such as about 0.4 to 0.6dl/g, and the viscosity of the fourth polylactic acid may be, but is not limited to, about 1.1 to 3.0dl/g, such as about 1.6 to 2.4 dl/g.
Further, the polyethylene glycol in the above-mentioned third polymeric material may include polyethylene glycols of different average molecular weights and any combination thereof. For example, the polyethylene glycol in the third polymer material example may include a fifth polyethylene glycol, a sixth polyethylene glycol or a combination thereof, wherein the fifth polyethylene glycol and the sixth polyethylene glycol may have different average molecular weights. The average molecular weight of the fifth polyethylene glycol can be about 100-1,000, such as about 285-315, but not limited thereto, and the average molecular weight of the sixth polyethylene glycol can be about 4,000-10,000, such as about 5,000-7,000, but not limited thereto.
In an embodiment, in the protective layer, the third polymer material may include polylactic acid. In this embodiment, the polylactic acid may be the third polylactic acid, the fourth polylactic acid, or a combination thereof.
In another embodiment, in the above-mentioned protective layer, the third polymer material may include both polylactic acid and polyethylene glycol. In this embodiment, the polylactic acid may be the third polylactic acid or the fourth polylactic acid, and the polyethylene glycol may be the fifth polylactic acid, the sixth polylactic acid, or a combination thereof. In this embodiment, the weight ratio of the polylactic acid to the polyethylene glycol in the protective layer may be about 1:0.05-1, such as, but not limited to, about 1:0.1, about 1:0.2, about 1:0.25, about 1:0.3, about 1:0.4, about 1:0.43, about 1:0.5, about 1:0.75, etc.
In a specific embodiment, the third polymeric material may include both polylactic acid and polyethylene glycol, the polylactic acid may be the third polylactic acid or the fourth polylactic acid, and the polyethylene glycol may be the fifth polyethylene glycol or the sixth polyethylene glycol.
In another specific embodiment, the third polymeric material may include both polylactic acid and polyethylene glycol, the polylactic acid may be the third polylactic acid or the fourth polylactic acid, and the polyethylene glycol may be a combination of the fifth polyethylene glycol and the sixth polyethylene glycol. In this particular embodiment, the weight ratio of the fifth polyethylene glycol to the sixth polyethylene glycol may be about 1:0.05-20, such as 1:0.1, 1:0.2, 1:0.5, 1:1, 1:5, 1:10, 1:15, etc., but is not limited thereto.
The anti-sticking layer of the disclosed drug-containing multilayer film may have a thickness of about 1-20 μm, such as about 1-13 μm, but is not limited thereto.
In one embodiment, the disclosed medicated multilayer film has a medicated layer and an anti-stick layer, and the thickness thereof may be about 15-110 μm, such as about 45-60 μm, but is not limited thereto. In another embodiment, the disclosed medicated multilayer film has a medicated layer and an anti-stick layer, and the thickness thereof may be about 16-130 μm, such as about 45-70 μm, but is not limited thereto.
The present disclosure also provides a method for forming a multi-layer film containing a drug, which can be used to form the multi-layer film containing a drug of the present disclosure.
The method for forming the multi-layer film containing drug of the present disclosure includes, but is not limited to, the following method (a) or (b).
See figure 1. FIG. 1 shows an embodiment of a method for forming a multi-layer film containing a drug according to the present disclosure, as in method (a).
The means (a) may include the following steps, but is not limited thereto.
First, a first solution is dried to form a film, so as to form a drug-containing layer 101. The medicine-containing layer contains medicine D and has one surface S1 and the other surface S2.
Then, a second solution is dried to form a film on the surface S1 of the drug-containing layer 101 to form an anti-sticking layer 103, and the preparation of the drug-containing multilayer film 100 according to an embodiment of the present disclosure is completed.
See also fig. 2. FIG. 2 shows another embodiment of the method for forming a multi-layer film containing a drug according to the present disclosure, as in the method (b).
The method (b) may include the following steps, but is not limited thereto.
First, a second solution is dried to form a film, so as to form an anti-sticking layer 103.
Then, a first solution is dried to form a film on the anti-sticking layer 103 to form a drug-containing layer 101, and the preparation of the drug-containing multilayer film 100 according to an embodiment of the present disclosure is completed. The drug-containing layer 101 contains a drug D.
The solute of the first solution may comprise a first composition. The first composition may include, but is not limited to, a first polymer material and a drug. Examples of the solvent of the first solution include, but are not limited to, dichloromethane, tetrahydrofuran, chloroform, and the like.
The content of the first polymer material in the first solution may be about 5-30 wt%, for example, about 10-25 wt%, about 15 wt%, about 20 wt%, etc., but is not limited thereto. The weight ratio of the first polymer material to the drug may be about 1:0.01 to 0.3, for example, about 1:0.015, 1:0.02, 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, but is not limited thereto.
The solute of the second solution may comprise a second composition. The second composition may include, but is not limited to, a second polymer material. Examples of the solvent of the second solution include, but are not limited to, dichloromethane, tetrahydrofuran, chloroform, etc.
The content of the second polymer material in the second solution may be about 5-30 wt%, for example, about 10-25 wt%, about 15 wt%, about 20 wt%, etc., but is not limited thereto.
Regarding the first composition, the first polymer material and the drug related to the first solution can be respectively identical to the first composition, the first polymer material and the drug of the drug-containing layer of the drug-containing multilayer film of the present disclosure described above, and therefore, all the related descriptions thereof can be found in the preceding paragraphs, and the related descriptions of the first composition, the first polymer material and the drug of the drug-containing layer of the drug-containing multilayer film of the present disclosure are not repeated herein.
Similarly, the second composition and the second polymer material related to the second solution can be respectively the same as the second composition and the first polymer material of the anti-adhesive layer of the drug-containing multilayer film of the present disclosure described above, and therefore, all the related descriptions thereof can be found in the preceding paragraphs, and the related descriptions of the second composition and the second polymer material of the anti-adhesive layer of the drug-containing multilayer film of the present disclosure are also not repeated herein.
In one embodiment, in the above aspect (a), the method for forming the drug-containing layer may include, but is not limited to, the following steps.
See figure 3. The first solution is poured onto a plate P having at least one groove R and dried to form a film on the plate P having at least one groove R to form a drug-containing layer 101 ', and the drug-containing layer 101 ' has at least one microstructure MS protruding from a surface S2 '.
In this embodiment, the anti-sticking layer 103 ' is then formed on the surface S1 ' of the drug-containing layer 101 '.
The recess of the plate may have an upper surface. The shape of the upper surface can be, but is not limited to, a curved surface, a flat plate, etc. The shape of the microstructure of the drug-containing layer is formed corresponding to the shape of the groove of the flat plate.
The aspect ratio of the groove may be about 1:2-4, such as 1:1, 1:1.5, 1:2, etc., but is not limited thereto.
In one embodiment, the plate has a plurality of grooves. In this embodiment, the distance from the center to the center of two adjacent grooves in the plurality of grooves may be about 50-2,000 μm, such as, but not limited to, about 75 μm, about 100 μm, about 150 μm, about 200 μm, about 220 μm, about 250 μm, about 300 μm, about 350 μm, about 400 μm, about 500 μm, about 1,000 μm, about 1,500 μm, etc.
In addition, in the embodiment where the flat plate has a plurality of grooves, the above-mentioned flat plate has a plurality of groovesThe density of the plurality of grooves may be about 0.1-100 grooves/cm2E.g., about 1-30 grooves/cm2About 0.01 groove/cm2About 0.25 grooves/cm2About 0.5 grooves/cm2About 1 groove/cm2About 2 grooves/cm2About 3 grooves/cm2About 4 grooves/cm2About 5 grooves/cm2About 9 grooves/cm2About 10 grooves/cm2About 13 grooves/cm2About 15 grooves/cm2About 16 grooves/cm2About 20 grooves/cm2About 25 grooves/cm2About 29 grooves/cm2About 30 grooves/cm2About 35 grooves/cm2About 36 grooves/cm2About 49 grooves/cm2About 50 grooves/cm2About 60 grooves/cm2About 64 grooves/cm2About 65 grooves/cm2About 70 grooves/cm2About 75 grooves/cm2About 80 grooves/cm2About 81 grooves/cm2About 90 grooves/cm2About 100 grooves/cm2But is not limited thereto.
In addition, in the embodiment where the plate has a plurality of grooves, the shape and/or the manner of the plurality of grooves of the plate are not particularly limited, and can be adjusted as required. For example, the shape of the plurality of grooves may include, but is not limited to, a rectangle, a circle, a triangle, and an irregular shape, or the plurality of grooves may be uniformly or non-uniformly distributed on the plate. In a specific embodiment, the plurality of grooves of the plate are arranged in a matrix.
The material of the flat plate is not particularly limited as long as it can form a groove of a desired shape without being dissolved or eroded by the second solution and can peel off the formed thin film therefrom without damaging the thin film. Examples of the material of the plate include, but are not limited to, stainless steel, glass, teflon, etc.
The microstructure of the drug-containing layer formed by the grooves of the corresponding plate can be the same as the microstructure of the drug-containing layer of the disclosed drug-containing multilayer film, and therefore, all the related descriptions can be found in the preceding paragraphs, and will not be repeated herein.
See also fig. 4. In an embodiment of the method for forming a multi-layer film containing a drug of the present disclosure, the methods (a) and (b) may further include, but are not limited to, drying a third solution to form a film on the drug-containing layer 101 after forming the drug-containing layer 101 and the anti-sticking layer 103 to form a protective layer 105, so as to form the multi-layer film containing a drug 200, wherein the drug-containing layer is located between the anti-sticking layer and the protective layer.
See also fig. 5. In a specific embodiment of the method for forming a multi-layer film containing a drug of the present disclosure, in the case that the formed drug-containing layer has a microstructure, after forming both the drug-containing layer 101 ' and the anti-sticking layer 103 ', the third solution is dried to form a film on the microstructure-containing surface S2 ' of the drug-containing layer 101 ' having a microstructure to form a protective layer 105 ', so as to form a multi-layer film containing a drug 200 ', wherein the drug-containing layer 101 ' is located between the anti-sticking layer 103 ' and the protective layer 105 '.
The solute of the third solution may comprise a third composition. The third composition may include, but is not limited to, a third polymeric material. Examples of the solvent of the third solution include, but are not limited to, dichloromethane, tetrahydrofuran, chloroform, etc.
Also, the content of the third polymer material in the third solution may be about 5 to 30 wt%, for example, about 10 to 25 wt%, about 15 wt%, about 20 wt%, etc., but is not limited thereto.
Regarding the third composition and the third polymeric material related to the third solution can be respectively identical to the third composition and the third polymeric material of the drug-containing layer of the disclosed drug-containing multilayer film, and therefore, all the related descriptions thereof can be found in the preceding paragraphs, and the related descriptions of the third composition and the third polymeric material of the protective layer of the disclosed drug-containing multilayer film are not repeated herein.
Examples
A. Anti-sticking film
A-1 preparation of anti-sticking film
Each anti-tack film was prepared according to the formulation of table 1 below.
TABLE 1
Figure BDA0002353796750000131
Polyethylene glycol 300: the average molecular weight of the polyethylene glycol is 285-315;
polyethylene glycol 6000: the average molecular weight of the polyethylene glycol is 5,000-10,000;
-: no addition was made.
First, polylactic acid and polyethylene glycol were dissolved in methylene chloride and mixed uniformly to form a solution having a total high molecular content of 11 wt%.
Then, the solution was poured onto a glass plate and uniformly coated on the surface of the glass plate by an automatic film coater and a coating ruler (scale: 230 μm).
And then placing the glass plate in an air extraction cabinet to volatilize dichloromethane so as to form the anti-sticking film.
A-2 anti-sticking test of anti-sticking film
A-2-1. cell assay
1. Method of producing a composite material
The cells used in this assay were L929 cells.
(1) Observation of cell appearance
First, the anti-stick film (BM) was cut to a suitable size and placed in the wells of a 24-well plate and a cell suspension was added to the wells. The 24-hole disk was then displaced by 5% CO2Culturing is carried out in a cell culture chamber at 37 ℃. After 24 hours of culture, the appearance of the cells was photographed by a microscope. In the control group, only the culture dish was added with the cell suspension.
(2) Cell viability assay
Cell viability assays were performed with the MTT assay.
First, the anti-stick film (BM) was cut to size and placed in the wells of a 96-well plate and cell suspension was added to the wells. The 96-well plate was then displaced at 5% CO2Culturing was carried out in a cell culture chamber at 37 ℃. In the control group, only the culture dish was added with the cell suspension. Blank group is simple culture medium.
After 24 hours of incubation, the original culture broth in the plate was removed, and then fresh culture broth containing MTT reagent was added to the plate. The plates were then placed in 5% CO2A cell culture chamber at 37 ℃ for 4 hours.
Finally, the culture medium in the culture dish is removed and HCl/iso-propanol is added to dissolve the intracellular products, and the absorbance of each well at 570nm is analyzed by a microplate spectrometer (microplate reader).
2. Results
(1) Observation of cell appearance
The results are shown in FIG. 6A.
As shown in FIG. 6A, in the control group in which only the culture dish was used for the culture, the cells adhered to the culture dish and grown, whereas in the experimental group in which the anti-sticking film was present in the culture dish, the cells were hardly adhered to the anti-sticking film and were only suspended in the culture solution. The results show that the anti-adhesion layer of the present disclosure has the effect of preventing cell adhesion and growth.
(2) Cell viability assay
The results are shown in FIG. 6B.
FIG. 6B shows that the absorbance at 570nm of the control group cultured only with the culture dish reached about 0.5, whereas the absorbance at 570nm of the test group with the anti-sticking film was about the same as that of the simple culture medium, which indicates that the cells in the test group were hardly viable. This experiment also demonstrates that the anti-adhesive layer of the present disclosure prevents cell attachment and growth.
A-2-2 animal test
1. Method of producing a composite material
Anti-adhesion tests were performed on male Steady-Dow (Sprague-Dawley) rats.
First, rats were anesthetized with intraperitoneal injections of Zonetil (25mg/0.5ml/kg) and Xylazine (10mg/0.5 ml/kg).
Then in the ratThe right abdomen was operated to cut out to have a length of 1.5cm2A small opening and a small area of scratch made in the cecum and abdominal wall of the adjacent cecum (see left photograph of figure 7).
Thereafter, the rats were divided into three groups, which were control group, experimental group 1 and experimental group 2, respectively, and 10 rats were used per group. In the control group, rats were not implanted with any membrane. In experimental group 1, rats were implanted with the anti-sticking film AM prepared in the front, and in experimental group 2, rats were implanted with the anti-sticking film BM prepared in the front. In both experimental group 1 and 2, the membrane was implanted between the cecum and abdominal wall of the rat (see right photograph in fig. 7). After the surgery was completed, the cecum of the rat was sutured to the abdominal wall.
After the operated rats were continuously raised for one month, the rats were anesthetized to photograph the cecum and abdominal wall of the operation site and to observe the degree of adhesion. Thereafter, the severity of adhesion between the cecum and abdominal wall of each group of rats was determined and analyzed according to the criteria shown in Table 2 below.
TABLE 2 severity of adhesion based on the ratio of adhesion rating to injured cecal surface area (Shmuel Avital. et al., Dis Colon Rectum,48: 153-
Figure BDA0002353796750000151
0 is no sticking; 1 is thin, threadlike and easy to separate; 2 ═ thick, sticky, difficult to cut, and when separated, does not tear the organ; thick, sticky, non-incisable, and when separated, tears the organ.
"absence of adhesions" is defined as complete absence of adhesions from the cecum to the abdominal wall.
"light adhesions" are defined as all grade 1 adhesions between the cecum and abdominal wall.
"moderate adhesion" includes all grade 2 adhesions between the cecum and abdominal wall and any grade 3 adhesion involving an abraded wall of the cecum having less than 100% adhesion area.
"Severe adhesions" refer to any grade 3 adhesions where the abraded wall of the cecum has 100% adhesion area.
2. Results
The results are shown in FIG. 8A and FIG. 8B.
Fig. 8A shows that there was severe adhesion between the cecum and abdominal wall of the rats in the control group, only a small amount of filamentous adhesion between the cecum and abdominal wall of the rats in experimental group 1 (anti-adhesion film AM), and only slight adhesion between the cecum and abdominal wall of the rats in experimental group 2 (anti-adhesion film BM). Specifically, compared to the control rats with a lot of connective tissues connected together between the cecum and the abdominal wall, which results in a severe adhesion condition, the rats in experimental groups 1 and 2 have less connective tissue formation between the cecum and the abdominal wall due to the anti-adhesion film of the present disclosure as a barrier, and thus the adhesion degree is not significant.
Figure 8B shows the percentage of the number of rats with mild and moderate or severe adhesions in each group. Fig. 8B shows that 80% of rats were moderately or heavily stained in the control group, only 15% of rats in experimental group 1(AM) were moderately stained in grade 2 to grade 3, the rest were slightly stained in grade 1, and even all rats in experimental group 2(BM) were moderately stained in grade 1.
From the above results, it is known that the anti-blocking effect of the film made of polylactic acid with high viscosity (viscosity 1.6-2.4dl/g) can be achieved.
B. Multilayer film containing medicine
B-1 preparation of a multilayer film containing a drug
B-1-1 preparation of a drug-containing multilayer film (drug-containing layer having a flat surface) (a) preparation method 1
Each of the drug-containing multilayer films was prepared according to the formulation shown in Table 3 below.
TABLE 3
Figure BDA0002353796750000161
Figure BDA0002353796750000171
(1) Preparation of anti-adhesive layer
First, polylactic acid was dissolved in methylene chloride and uniformly mixed to form a solution having a total high molecular weight content of 11 wt%.
Then, the solution was poured onto a glass plate and uniformly coated on the surface of the glass plate by an automatic film coater and a coating ruler (scale: 230 μm).
The glass plate was then placed in an air-extraction cabinet to evaporate the methylene chloride to form an anti-stick layer.
(2) Preparation of drug-containing layers
Dissolving polylactic acid in dichloromethane and mixing uniformly to form a polylactic acid solution.
If the components do not contain polyethylene glycol, lidocaine hydrochloride is added into the polylactic acid solution and uniformly mixed to form a mixed solution. If the components contain polyethylene glycol, the polyethylene glycol is added into the polylactic acid solution and mixed evenly, and then lidocaine hydrochloride is added into the polylactic acid and polyethylene glycol solution and mixed evenly to form a mixed solution. In the mixed solution, the total high molecular content was 20 wt%, and the drug content was 20% of the high molecular content.
Then, the mixed solution was poured onto the anti-sticking layer surface formed on the glass plate and uniformly coated on the anti-sticking layer by an automatic film scraper and a coating ruler (scale: 200 μm).
And then placing the glass plate in an air extraction cabinet to volatilize dichloromethane so as to form a medicine-containing layer on the anti-sticking layer. If the multi-layer film containing the drug has no protective layer, the preparation of the multi-layer film containing the drug is completed in this step. If the multilayer film containing a drug has a protective layer, the following procedure is continued.
(3) Protective layer
Dissolving polylactic acid in dichloromethane and mixing uniformly to form a polylactic acid solution.
If the components do not contain polyethylene glycol, the polylactic acid solution is poured on the drug-containing layer of the anti-sticking layer and the drug-containing layer on the glass plate, and is uniformly coated on the surface of the drug-containing layer by an automatic film scraper and a coating ruler (the scale is 100 mu m).
If the components contain polyethylene glycol, adding the polyethylene glycol into the polylactic acid solution and uniformly mixing to form a mixed solution, wherein the total high molecular weight content in the mixed solution is 20 wt%. Then, the mixed solution was poured onto the above-mentioned drug-containing layer of the anti-sticking layer and the drug-containing layer on the glass plate, and was uniformly applied onto the surface of the drug-containing layer by an automatic film-coating machine and a coating ruler (scale: 100 μm).
Then, the glass plate is placed in an air extraction cabinet to volatilize dichloromethane so as to form a protective layer on the drug-containing layer, and the preparation of the drug-containing multilayer film is completed.
(b) Preparation method 2
Each of the drug-containing multilayer thin films RM was prepared according to the formulation of Table 4 below.
TABLE 4
Figure BDA0002353796750000181
(1) Preparation of drug-containing layers
Firstly, polylactic acid is dissolved in dichloromethane and uniformly mixed to form a polylactic acid solution.
Adding polyethylene glycol into the polylactic acid solution, uniformly mixing, then adding lidocaine hydrochloride into the polylactic acid and polyethylene glycol solution, and uniformly mixing to form a mixed solution. In the mixed solution, the total high molecular content was 20 wt%, and the drug content was 20% of the high molecular content.
Then, the mixed solution was poured onto a glass plate and uniformly coated on the surface of the glass plate by an automatic film coater and a coating ruler (scale: 200 μm).
The glass plate was then placed in an air-extraction cabinet to evaporate the methylene chloride to form a drug-containing layer.
(2) Preparation of anti-adhesive layer
Polylactic acid was dissolved in methylene chloride and mixed well to form a solution with a total high molecular weight content of 11 wt%.
Then, the solution was poured onto the above-mentioned drug-containing layer on a glass plate, and uniformly coated on the surface of the drug-containing layer by an automatic film-coating machine and a coating ruler (scale: 230 μm).
And then placing the glass plate in an air extraction cabinet to volatilize dichloromethane so as to form an anti-sticking layer, thereby completing the preparation of the medicine-containing multilayer film RM.
The drug-containing multilayer film RM can be surely formed in the production method 2 and can be peeled off from the glass plate as it is, see fig. 9.
B-1-2 preparation of a multilayer film containing a drug (drug-containing layer having a microstructure)
Each of the drug-containing multilayer films was prepared according to the formulation of Table 5 below.
TABLE 5
Figure BDA0002353796750000191
Figure BDA0002353796750000201
(1) Preparation of drug-containing layers
(i) Manufacture of stainless steel mould
The surface of the stainless steel plate is processed to produce at least one groove on one surface thereof. The number of the grooves, the shape of the grooves and the arrangement of the plurality of grooves can be set according to the requirement. Therefore, the specification of the die can be customized, and the film containing the specific microstructure can be manufactured by the die turnover method.
In the present preparation, 3 stainless steel plate molds were fabricated, the grooves on the surfaces thereof were all the grooves having the upper surface with the arc-shaped curved surface, and the groove densities were 29 grooves/cm, respectively213 grooves/cm2And 3 grooves/cm2。
(ii) Preparation of drug-containing layers
Dissolving polylactic acid in dichloromethane and mixing uniformly to form a polylactic acid solution.
Adding polyethylene glycol into the polylactic acid solution, uniformly mixing, then adding lidocaine hydrochloride into the polylactic acid and polyethylene glycol solution, and uniformly mixing to form a mixed solution. In the mixed solution, the total high molecular content was 20 wt%, and the drug content was 20% of the high molecular content.
Then, the mixed solution was poured into the above stainless steel plate mold, and uniformly coated on the stainless steel plate mold by an automatic film scraper and a coating ruler (scale: 200 μm).
The stainless steel plate mold was then placed in an air-extraction cabinet to evaporate the methylene chloride (about 24 hours) to form a micro-structured drug-containing layer.
(2) Preparation of anti-adhesive layer
Polylactic acid was dissolved in methylene chloride and mixed uniformly to form a solution having a high molecular content of 11 wt%.
Then, the solution was poured onto the above-mentioned drug-containing layer on a stainless steel plate mold, and uniformly coated on the surface of the drug-containing layer by an automatic film scraper and coating ruler (scale: 230 μm).
Then, the stainless steel plate is placed in an air extraction cabinet to volatilize dichloromethane so as to form an anti-sticking layer. If the multi-layer film containing the drug has no protective layer, the preparation of the multi-layer film containing the drug is completed in this step. If the multilayer film containing a drug has a protective layer, the following procedure is continued.
(3) Protective layer
Dissolving polylactic acid and polyethylene glycol in dichloromethane, and mixing uniformly to form a mixed solution, wherein the total high molecular weight content in the mixed solution is 20 wt%.
Then, the two films of the chemical-containing layer and the anti-sticking layer on the stainless steel plate are removed from the stainless steel plate mold, and the two films of the chemical-containing layer and the anti-sticking layer are placed on the surface of a glass plate in a manner that the microstructure of the chemical-containing layer faces upwards.
The mixed solution is poured on the surface with microstructure of the two layers of the drug-containing layer and the anti-sticking layer, and is uniformly coated on the surface of the drug-containing layer by an automatic film scraper and a coating ruler (the scale is 100 mu m).
Then, the glass plate is placed in an air extraction cabinet, dichloromethane is volatilized to form a protective layer on the drug-containing layer, and the preparation of the drug-containing multilayer film is completed.
B-2 in vitro drug Release test for drug-containing multilayer films
1. Method of producing a composite material
The multilayer film containing the medicine is cut into proper sizes and placed in a tissue embedding box to fix the periphery of the film so as to avoid the phenomenon of curling of the film.
The tissue cassette was then placed in a glass vial containing 40ml of Phosphate Buffered Saline (PBS) and shaken at 100rpm to allow the membrane to release the drug under conditions that mimic the in vivo dynamic environment and sampling was performed at specific time points.
The release test is divided into an immediate release test and a sustained release test. The sampling times for the immediate release type were 0.5, 1, 2, 4, 6, 8 and 24 hours, while the sampling times for the sustained release test were 0.5, 1, 2, 4, 6, 8, 24, 48, 96, 168, 264 and 336 hours.
At each sampling 4ml of PBS was aspirated from the vial, after which the same volume of fresh PBS was added to maintain a total volume of 40ml of PBS. The sampled PBS was diluted and analyzed for drug content by an enzyme immunoassay analyzer (Elisa reader), and the cumulative amount of released drug at each time point of the film was determined by calculation.
In addition, to confirm the total drug content in each film, the film was cut into multiple small-sized pieces and placed in a glass sample vial.
Add 4ml PBS into the glass vial and perform ultrasonic vibration on the glass vial to extract the drug in the membrane for about 30 minutes. Thereafter, the concentration of the drug in PBS was analyzed by High Performance Liquid Chromatography (HPLC) to confirm the total amount of drug contained in the membrane.
The cumulative drug release rate (%) of the membrane at each time point was calculated by the following formula.
The cumulative drug release rate of the film at each time point
2. Results
(1) Results of immediate Release test for drug-containing multilayer films M-01, M-02, M-03, M-04, M-05 and M-06
The results of the immediate release test for the drug-containing multilayer films M-01, M-02, M-03, M-04, M-05 and M-06 are shown in FIG. 10.
As shown in fig. 10, when the main component of the drug-containing layer in the drug-containing multilayer film is low viscosity polylactic acid (0.4-0.6dl/g), the drug release profile of the drug-containing multilayer film shows the phenomenon of initial rapid release regardless of whether the drug-containing layer contains polyethylene glycol (polyethylene glycol 300, polyethylene glycol 6000 or a combination thereof), wherein the drug release rate in 1 hour is more than 40%, and the drug release rate in 24 hours is more than 80%.
The above results show that when the main component of the drug-containing layer is composed of polylactic acid (0.4-0.6dl/g) having low viscosity, the structure of the drug-containing layer is loose, and thus the drug is easily released from the film through a diffusion mechanism. Therefore, when the drug-containing layer is composed of polylactic acid (0.4 to 0.6dl/g) having low viscosity, the drug-containing multilayer film is suitable as an immediate release film.
(2) Results of immediate Release test for drug-containing multilayer films M-02, M-07, M-08, M-09, and M-10
In order to confirm the effect of the protective layers having different compositions on the drug release, the results of the immediate release test of the drug-containing multilayer film M-02 (without the protective layer) and the drug-containing multilayer films M-07, M-08, M-09, and M-10 (with the protective layer) are shown in FIG. 11.
As shown in FIG. 11, the cumulative release rate of the drug over 0 to 24 hours was reduced in the case of the drug-containing multilayer film M-07 having a protective layer made of polylactic acid (0.4 to 0.6dl/g) with a low viscosity as compared with the drug-containing multilayer film M-02 having no protective layer. When the component of the protective layer contains polyethylene glycol 300 or polyethylene glycol 6000, the cumulative release rate of the drug contained in the multilayer film does not show a tendency of decreasing, which indicates that the existence of polyethylene glycol can make the structure of the protective layer porous, and the effect of physical barrier is not obvious.
(3) Results of sustained Release test of drug-containing multilayer films M-11 and M-12
In order to confirm the effect of the viscosity of polylactic acid of the drug-containing layer in the drug-containing multilayer film and the protective layer on the drug release from the drug-containing multilayer film, the results of the release test of the drug-containing multilayer film M-02 (without the protective layer) and the drug-containing multilayer films M-11 and M-12 are shown in FIG. 12.
As can be seen from FIG. 12, the cumulative release rate of the drug at 0 to 1 hour of the drug-containing multilayer film M-11 composed of polylactic acid having a high viscosity (1.6 to 2.4dl/g) tends to be greatly reduced, and the cumulative release rate of the drug at 24 hours is also reduced from 85% to 32%, as compared with the drug-containing multilayer film M-05 composed of polylactic acid having a low viscosity (0.4 to 0.6dl/g) as the main component of the drug-containing layer.
Further, the multi-layer film containing a drug (M-11 and M12) composed of polylactic acid (1.6-2.4dl/g) having a high viscosity as the main component of the drug-containing layer did not show a remarkably rapid release phenomenon in the initial stage, and the cumulative release rate of the drug for 14 days was only 50% with the lapse of time, indicating that the drug in the multi-layer film containing a drug could be released continuously for 14 days or more. Cumulative drug release
This result shows that when the main component of the drug-containing layer is composed of polylactic acid (1.6-2.4dl/g) having high viscosity, the structure of the drug-containing layer is compact, and the time for releasing the drug from the film can be prolonged.
Therefore, when the drug-containing layer is composed of polylactic acid (1.6 to 2.4dl/g) having a high viscosity, the drug-containing multilayer film is suitable as a sustained-release film.
In addition, the results of the drug-containing multilayer films M-11 and M12 also showed that the drug-containing multilayer film M-12 with the protective layer showed no initial faster release (cumulative drug release rate of 0 to 1 hour) and its cumulative drug release rate of 14 days was only about 40%, compared to the drug-containing multilayer film M-11 without the protective layer. It was shown that, in the case where the main component of the drug-containing layer is composed of polylactic acid (1.6-2.4dl/g) having high viscosity, the presence of the protective layer can further reduce the cumulative drug release rate of the drug and prolong the drug release time.
(4) Results of sustained Release test of drug-containing multilayer films M-11, MS-1, MS-2 and MS-3
In order to confirm the effect of microstructure of the drug-containing layer in the drug-containing multilayer film on the drug release from the drug-containing multilayer film, the results of the release test for the drug-containing multilayer film M-11 (without microstructure of the drug-containing layer) and the drug-containing multilayer films MS-1, MS-2 and MS-3 are shown in FIG. 13.
When the number of microstructures of the drug-containing layer is increased, the cumulative release rate of the drug is correspondingly increased. The cumulative drug release rate of the drug-containing multilayer film (MS-1) having the maximum number of microstructures per unit area of the drug-containing layer reaches 100% in 14 days, which is increased by 50% compared with the drug-containing multilayer film (M-11) having no microstructures in the drug-containing layer.
In contrast, as the number of microstructures per unit area of the drug-containing layer decreases, the magnitude of increase in the cumulative drug release rate also decreases. Compared with the drug-containing multilayer film M-11 with a drug-containing layer without a microstructure, the cumulative release rates of the drug-containing multilayer films MS-2 and MS-3 are respectively increased by 30 percent and 20 percent in 14 days.
Also, the results of SEM analysis of the drug-containing multilayer films MS-1, MS-2 and MS-3 are shown in FIG. 14.
(5) Results of sustained Release test of drug-containing multilayer films MS-1, MS-2, MS-1-B and MS-2-B
In order to confirm the effect of the protective layer on the drug release of the drug-containing multilayer film having the micro-structured drug-containing layer, the results of the release test of the drug-containing multilayer films MS-1, MS-2, MS-1-B and MS-2-B are shown in FIG. 15.
As can be seen from FIG. 15, the cumulative release rate at day 14 of the drug-containing multilayer film MS-1-B with the protective layer was decreased from 100% to 50% as compared with the drug-containing multilayer film MS-1, while the cumulative release rate at day 14 of the drug-containing multilayer film MS-2-B with the protective layer was decreased from 80% to 40% as compared with the drug-containing multilayer film MS-2.
Also, the results of SEM analysis of the drug-containing multilayer films MS-1-B and MS-2-B are shown in FIG. 16.
As shown in FIG. 16, the microstructure of the drug-containing layers of the multi-layer films MS-1-B and MS-2-B containing drugs is covered by the protective layer, so that the surface area is greatly reduced, and thus the drugs are less likely to diffuse out of the films, thereby reducing the cumulative release rate of the drugs.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (32)

1. A medicated multilayer film comprising:
a drug-containing layer; and
an anti-sticking layer on the surface of the drug-containing layer,
wherein the drug-containing layer is composed of a first composition, the first composition comprises a first polymer material and a drug, the first polymer material comprises at least one selected from the group consisting of:
polylactic acid (PLA) and polyethylene glycol (PEG), wherein the weight ratio of the first polymer material to the drug is 1:0.01-0.3,
wherein the anti-sticking layer is composed of a second composition, the second composition comprises a second polymer material, the second polymer material comprises at least one selected from the group consisting of:
polylactic acid and polyethylene glycol.
2. The medicated multilayer film of claim 1, wherein the first polymeric material comprises the polylactic acid, and the polylactic acid is a first polylactic acid or a second polylactic acid, wherein the viscosity of the first polylactic acid is 0.05 to 1dl/g, and the viscosity of the second polylactic acid is 1.1 to 3.0 dl/g.
3. The medicated multilayer film of claim 2, wherein the first polymeric material is the polylactic acid, and the polylactic acid is the first polylactic acid, and the drug comprises:
an analgesic, an anti-inflammatory analgesic, or a combination thereof.
4. The medicated multilayer film of claim 2, wherein the first polymeric material is the polylactic acid and the polylactic acid is the second polylactic acid, and the drug comprises:
an analgesic, an antibiotic, or a combination thereof.
5. The medicated multilayer film of claim 1, wherein the first polymeric material comprises the polylactic acid and the polyethylene glycol, and the polylactic acid is the first polylactic acid or the second polylactic acid, and the polyethylene glycol is the first polyethylene glycol, the second polyethylene glycol or a combination thereof, wherein the viscosity of the first polylactic acid is 0.05-1dl/g, and the viscosity of the second polylactic acid is 1.1-3.0dl/g, and wherein the average molecular weight of the first polyethylene glycol is 100-1,000, and the average molecular weight of the first polyethylene glycol is 4,000-10,000.
6. The medicated multilayer film of claim 5, wherein the weight ratio of the polylactic acid to the polyethylene glycol in the first polymeric material is 1: 0.05-1.
7. The medicated multilayer film of claim 5, wherein the first polymeric material is a combination of the polylactic acid and the polyethylene glycol, the polylactic acid is a first polylactic acid or a second polylactic acid, and the polyethylene glycol is the first polyethylene glycol or the second polyethylene glycol.
8. The drug-containing multilayer film of claim 7, wherein the polylactic acid is the first polylactic acid, and the drug comprises:
an analgesic, an anti-inflammatory analgesic, or a combination thereof.
9. The medicated multilayer film of claim 7, wherein the polylactic acid is the second polylactic acid, and the drug comprises:
an analgesic, an antibiotic, or a combination thereof.
10. The medicated multilayer film of claim 5, wherein the first polymeric material is a combination of the polylactic acid and the polyethylene glycol, the polylactic acid is the first polylactic acid or the second polylactic acid, and the polyethylene glycol is a combination of the first polyethylene glycol and the second polyethylene glycol, and wherein the weight ratio of the first polyethylene glycol to the second polyethylene glycol is 1: 0.01-10.
11. The medicated multilayer film of claim 10, wherein the polylactic acid is the first polylactic acid, and the drug comprises:
an analgesic, an anti-inflammatory analgesic, or a combination thereof.
12. The medicated multilayer film of claim 10, wherein the polylactic acid is the second polylactic acid, and the drug comprises:
an analgesic, an antibiotic, or a combination thereof.
13. The drug-containing multilayer film of claim 1, wherein the drug-containing layer has a plurality of microstructures protruding from the other surface thereof.
14. The medicated multilayer film of claim 13, wherein the microstructure has an upper surface, and the shape of the upper surface comprises a curved surface or a flat surface.
15. The drug-containing multilayer film of claim 13, wherein the ratio of the height of the microstructures to the width of the base is 1: 2-4.
16. The drug-containing multilayer film of claim 13, wherein the drug-containing layer has a plurality of microstructures.
17. The medicated multilayer film of claim 16, wherein the microstructures have a density of 0.1 to 100/cm on the medicated layer2。
18. The medicated multilayer film of claim 1, wherein the second polymeric material comprises polylactic acid, and the viscosity of polylactic acid is 1.1-3.0 dl/g.
19. The drug-containing multilayer film of claim 1, wherein the second polymer material comprises the polylactic acid and the polyethylene glycol, and the polyethylene glycol is a third polyethylene glycol, a fourth polyethylene glycol or a combination thereof, wherein the viscosity of the polylactic acid is 0.05-1dl/g, and wherein the average molecular weight of the third polyethylene glycol is 100-.
20. The medicated multilayer film of claim 1, further comprising a protective layer on the other surface of the medicated layer, wherein the medicated layer is located between the anti-sticking layer and the protective layer,
and wherein the protective layer is formed of a third composition comprising a third polymeric material, the third polymeric material comprising at least one selected from the group consisting of:
polylactic acid and polyethylene glycol.
21. The medicated multilayer film of claim 20, wherein the third polymeric material comprises the polylactic acid, and the polylactic acid is a third polylactic acid or a fourth polylactic acid, wherein the viscosity of the third polylactic acid is 0.05 to 1dl/g and the viscosity of the fourth polylactic acid is 1.1 to 3.0 dl/g.
22. The medicated multilayer film of claim 20, wherein the third polymeric material comprises the polylactic acid and the polyethylene glycol, and the polylactic acid is a third polylactic acid or a fourth polylactic acid, and the polyethylene glycol is a fifth polyethylene glycol, a sixth polyethylene glycol or a combination thereof, wherein the viscosity of the third polylactic acid is 0.05-1dl/g, and the viscosity of the fourth polylactic acid is 1.1-3.0dl/g, and wherein the average molecular weight of the fifth polyethylene glycol is 1,000 and the average molecular weight of the sixth polyethylene glycol is 4,000-10,000.
23. The medicated multilayer film of claim 22, wherein the third polymeric material is a combination of the polylactic acid and the polyethylene glycol, the polylactic acid is a third polylactic acid or a fourth polylactic acid, and the polyethylene glycol is the fifth polyethylene glycol or the sixth polyethylene glycol.
24. The medicated multilayer film of claim 22, wherein the third polymeric material is a combination of the polylactic acid and the polyethylene glycol, and the polylactic acid is the third polylactic acid or the fourth polylactic acid, and the polyethylene glycol is a combination of the fifth polyethylene glycol and the sixth polyethylene glycol, and wherein the weight ratio of the fifth polyethylene glycol to the sixth polyethylene glycol is 1: 0.05-10.
25. A method for forming a multilayer film containing a drug, comprising the following mode (a) or mode (b):
mode (a), comprising:
(i) drying the first solution to form a film so as to form a medicine-containing layer; and
(ii) drying the second solution to form a film on the surface of the medicine-containing layer so as to form an anti-sticking layer;
mode (b), comprising:
(i') drying the second solution to form a film to form an anti-stick layer; and
(ii') drying the first solution to form a film on the anti-sticking layer to form a drug-containing layer,
wherein the solute of the first solution comprises a first polymer material and a drug, the first polymer material comprising at least one selected from the group consisting of:
the polylactic acid and the polyethylene glycol are mixed,
the content of the first polymer material in the first solution is 5-30 wt%, the weight ratio of the first polymer material to the drug is 1:0.01-0.3,
further, wherein the solute of the second solution comprises a second polymer material comprising at least one selected from the group consisting of:
the polylactic acid and the polyethylene glycol are mixed,
and the content of the second polymer material in the second solution is 5-30 wt%.
26. The method of forming a drug-containing multilayer film according to claim 25, wherein the first polymeric material comprises the polylactic acid, and the polylactic acid is a first polylactic acid or a second polylactic acid, wherein the viscosity of the first polylactic acid is 0.05 to 1dl/g, and the viscosity of the second polylactic acid is 1.1 to 3.0 dl/g.
27. The method for forming a drug-containing multilayer film as claimed in claim 25, wherein the first polymer material comprises the polylactic acid and the polyethylene glycol, and the polylactic acid is the first polylactic acid or the second polylactic acid, and the polyethylene glycol is the first polyethylene glycol, the second polyethylene glycol or the combination thereof, wherein the viscosity of the first polylactic acid is 0.05-1dl/g, and the viscosity of the second polylactic acid is 1.1-3.0dl/g, and wherein the average molecular weight of the first polyethylene glycol is 100-1,000, and the average molecular weight of the first polyethylene glycol is 4,000-10,000.
28. The method according to claim 25, wherein in the aspect (a), the method for forming the drug-containing layer comprises:
pouring the first solution onto a flat plate with at least one groove, and drying the flat plate with at least one groove to form a film, so that the drug-containing layer has at least one microstructure protruding from the other surface thereof.
29. The method according to claim 28, wherein the groove has an upper surface, and the shape of the upper surface includes a curved surface or a flat surface.
30. The method of forming a drug-containing multilayer film according to claim 25, wherein the second polymeric material comprises polylactic acid, and the viscosity of the polylactic acid is about 1.1 to 3.0 dl/g.
31. The method for forming a drug-containing multilayer film as claimed in claim 25, wherein the second polymer material comprises the polylactic acid and the polyethylene glycol, and the polyethylene glycol is a third polyethylene glycol, a fourth polyethylene glycol or a combination thereof, wherein the viscosity of the polylactic acid is 0.05-1dl/g, and wherein the average molecular weight of the third polyethylene glycol is about 100-.
32. The method for forming a drug-containing multilayer film according to claim 25, wherein
The modes (a) and (b) further include:
(iii) drying the third solution to form a film on the medicine-containing layer to form a protective layer, wherein the medicine-containing layer is positioned between the anti-sticking layer and the protective layer,
further, wherein the solute of the third solution comprises a third high molecular material comprising at least one selected from the group consisting of:
the polylactic acid and the polyethylene glycol are mixed,
and the third polymeric material is present in the third solution in an amount of about 5-30 wt%.
CN202010001917.9A 2019-12-31 2020-01-02 Multilayer film containing medicine and method for forming the same Pending CN113116864A (en)

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