TW202126286A - Drug-containing multilayer film and method for forming the same - Google Patents

Abstract

A drug-containing multilayer film provided. The drug-containing multilayer film includes: a drug-containing layer; and an anti-adhesion layer on a surface of the drug-containing layer. The drug-containing layer is composed of a first composition including a first polymer material and a drug, and the first polymer material includes 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-adhesion layer is composed of a second composition, and the second composition includes a second polymer material, and the second polymer material includes at least one selected from the group consisting of polylactic acid and polyethylene glycol.

Description

Medicine-containing multilayer film and its forming method

This disclosure relates to medical films, and particularly relates to a drug-containing multilayer film and its forming method.

According to research, post-surgery sticking can cause a variety of complications, such as small intestine obstruction, chronic pelvic pain, infertility, etc. Therefore, avoiding sticking after surgery can not only reduce the discomfort and reduction that may occur in the subsequent patients The risk of having to accept another operation due to sticking problems can also save the expenditure of medical resources.

In addition to the sticking caused by surgery, pain or infection may also occur during wound repair after surgery. Therefore, drugs, such as painkillers and antibiotics, are needed to alleviate the discomfort of patients.

At present, postoperative pain relief methods mainly include intramuscular injection, intravenous injection, patient-controlled analgesia, and continuous epidural analgesia. Both the intramuscular injection method and the intravenous injection method require repeated administration of drugs within a few hours to maintain the pain relief effect, but they can also cause side effects.

Therefore, there is an urgent need for medical equipment that can simultaneously reduce or avoid the sticking and discomfort caused by surgery.

The present disclosure provides a drug-containing multilayer film, which includes: a drug-containing layer; and an anti-adhesion layer, and the anti-adhesion layer is on a surface of the drug-containing layer. The drug-containing layer is composed of a first composition including a first polymer material and a drug, and the first polymer material includes at least one selected from the group consisting of: poly Lactic 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-adhesion 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, including the following method (a) or method (b). Method (a) includes: (i) drying a first solution into a film to form a drug-containing layer; and (ii) drying a second solution to form a film on one surface of the drug-containing layer to form The first anti-adhesion layer. Method (b) includes: (i') drying a 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 includes a first polymer material and a drug, the first polymer material includes at least one selected from the group consisting of polylactic acid and polyethylene glycol, and the first polymer material The content 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 includes a second polymer material, and the second polymer material includes at least one selected from the group consisting of polylactic acid and polyethylene glycol, and the second polymer material is in the first The content in the second solution is about 5-30 wt%.

In order to make the above and other objects, features, and advantages of the present invention more obvious and understandable, the following is a detailed description of the preferred embodiments together with the accompanying drawings:

The present disclosure provides a drug-containing multilayer film. The drug-containing multilayer film of the present disclosure is a biodegradable non-fibrous film, and does not need to be fixed by sutures or other means, and can be well attached to surgical wounds or diffuse wounds and prevent tissue fluid leakage. In addition, the drug-containing multilayer film of the present disclosure has an anti-adhesion effect, which can prevent undesired tissue adhesion from occurring, and at the same time can release the required drugs to the wound or tissue area to which the film is attached, so as to achieve the required medical treatment effect.

The above-mentioned drug-containing multilayer film of the present disclosure may include, but is not limited to, a drug-containing layer and an anti-adhesion layer, and the anti-adhesion layer is located on one surface of the above-mentioned drug-containing layer.

The above-mentioned drug-containing layer may be composed of a first composition. The above-mentioned first composition may include a first polymer material and a drug, but is not limited thereto. In an embodiment, the weight ratio of the first polymer material to the drug may 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, etc., but not Limited to this.

Examples of the foregoing first polymer material may include, but are not limited to, polylactic acid (PLA), polyethylene glycol (PEG), etc., or any combination of the foregoing.

The polylactic acid in the example of the first polymer material mentioned above may include polylactic acid with different viscosities and any combination thereof. For example, the polylactic acid in the above examples 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 about 0.05-1 dl/g, for example, about 0.4-0.6 dl/g, etc., but not limited thereto, and the viscosity of the second polylactic acid may be about 1.1-3.0 dl/g, for example , About 1.6-2.4 dl/g, but not limited to this.

In addition, the polyethylene glycol in the example 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 example of the first polymer material may include a first polyethylene glycol, a second polyethylene glycol or a combination thereof, wherein the first polyethylene glycol and the second polyethylene glycol The diols can have different average molecular weights. The average molecular weight of the first polyethylene glycol may be about 100-1,000, for example, about 285-315, but not limited thereto, and the average molecular weight of the second polyethylene glycol may be about 4,000-10,000, for example, about 5,000 -7,000 etc., but not limited to this.

In one embodiment, in the above-mentioned drug-containing layer, the first polymer material includes polylactic acid. In this embodiment, the polylactic acid may be the above-mentioned first polylactic acid, a second polylactic acid, or a combination thereof.

In another embodiment, in the above-mentioned drug-containing layer, the first polymer material may include both polylactic acid and polyethylene glycol. In this embodiment, the polylactic acid may be the above-mentioned first polylactic acid or the above-mentioned second polylactic acid, and the polyethylene glycol may be the above-mentioned first polyethylene glycol, the above-mentioned second polyethylene glycol, or a combination thereof. In this embodiment, in the above-mentioned drug-containing layer, the weight ratio of polylactic acid to polyethylene glycol may be about 1:0.05-1, for example, 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., but not limited thereto.

Furthermore, in a specific embodiment, the first polymer material may include both polylactic acid and polyethylene glycol, and the polylactic acid may be the above-mentioned first polylactic acid or the above-mentioned second polylactic acid, and the polyethylene glycol may be The above-mentioned first polyethylene glycol or the above-mentioned 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 above-mentioned first polylactic acid or the above-mentioned second polylactic acid, and the polyethylene glycol may be the above-mentioned A combination of the first polyethylene glycol and the above-mentioned 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 not limited to this.

In addition, there are no particular restrictions on the drug in the drug-containing layer of the drug-containing multilayer film of the present disclosure, and it can be selected as required, as long as it can be released through the drug-containing multilayer film of the present disclosure and does not interfere with the drug-containing multilayer film of the present disclosure. Other components in the layer produce negative effects, such as affecting the formation of the drug-containing layer or inactivating the drug.

Examples of drugs in the drug-containing layer may include analgesics, anti-inflammatory analgesics, antibiotics, etc., but are not limited thereto. Analgesics may include, but are not limited to, lidocaine hydrochloride, morphine hydrochloride, fentanyl, and the like. Anti-inflammatory analgesics may include, but are not limited to, nonsteroidal anti-inflammatory drugs (NSAID), such as ibuprofen, naproxen, aspirin, Fenbufen, indometacin, diclofenac sodium, etc. Antibiotics may include, but are not limited to, vancomycin, rifampin, and the like.

In a specific embodiment, in the drug-containing multilayer film of the present disclosure, the first polymer material in the drug-containing layer is polylactic acid, and the polylactic acid is the above-mentioned viscosity of about 0.05-1 dl/g. A polylactic acid, and the drug in the drug-containing layer may include analgesics, anti-inflammatory analgesics, or a combination thereof. Furthermore, in this specific embodiment, the drug-containing multilayer film of the present disclosure has the effect of immediately releasing the drug.

In another specific embodiment, in the drug-containing multilayer film of the present disclosure, the first polymer material in the drug-containing layer is polylactic acid, and the polylactic acid has a viscosity of about 1.1-3.0 dl/g. The second polylactic acid, and the drug in the drug-containing layer may include analgesics, antibiotics, or a combination thereof. Moreover, in this specific embodiment, the drug-containing multilayer film of the present disclosure has the effect of continuously releasing the drug.

In another specific embodiment, in the drug-containing multilayer film of the present disclosure, the first polymer material in the drug-containing layer is a combination of polylactic acid and polyethylene glycol, and the viscosity of polylactic acid can be about 0.05-1 dl/g of the first polylactic acid, and polyethylene glycol is the first polyethylene glycol having an average molecular weight of about 100-1,000 or the second polyethylene glycol having an average molecular weight of about 4,000-10,000, The drugs in the drug-containing layer may include analgesics, anti-inflammatory analgesics, or a combination thereof. Furthermore, in this specific embodiment, the drug-containing multilayer film of the present disclosure has the effect of immediately releasing the drug.

In another specific embodiment, in the drug-containing multilayer film of the present disclosure, the first polymer material in the drug-containing layer is a combination of polylactic acid and polyethylene glycol, and the viscosity of polylactic acid can be about 1.1-3.0 dl/g of the second polylactic acid, and polyethylene glycol is the first polyethylene glycol having an average molecular weight of about 100-1,000 or the second polyethylene glycol having an average molecular weight of about 4,000-10,000, The medicine in the medicine-containing layer may include the above-mentioned analgesics, antibiotics or a combination thereof. Moreover, in this specific embodiment, the drug-containing multilayer film of the present disclosure has the effect of continuously releasing the drug.

In another specific embodiment, in the drug-containing multilayer film of the present disclosure, the first polymer material in the drug-containing layer is a combination of polylactic acid and polyethylene glycol, and the viscosity of polylactic acid can be about 0.05-1 dl/g of the first polylactic acid, and polyethylene glycol is the first polyethylene glycol having an average molecular weight of about 100-1,000 and the second polyethylene glycol having an average molecular weight of about 4,000-10,000 Combination, and the weight ratio of the first polyethylene glycol to the second polyethylene glycol is about 1:0.01-10. The medicine in the medicated layer may include analgesics, anti-inflammatory analgesics, or a combination thereof. Furthermore, in this specific embodiment, the drug-containing multilayer film of the present disclosure has the effect of immediately releasing the drug.

In another specific embodiment, in the drug-containing multilayer film of the present disclosure, the first polymer material in the drug-containing layer is a combination of polylactic acid and polyethylene glycol, and the viscosity of polylactic acid can be about 1.1-3.0 dl/g of the second polylactic acid, and polyethylene glycol is the first polyethylene glycol having an average molecular weight of about 100-1,000 and the second polyethylene glycol having an average molecular weight of about 4,000-10,000 Combined, and the weight ratio of the first polyethylene glycol to the second polyethylene glycol is about 1:0.01-20. The medicine in the medicine-containing layer may include the above-mentioned analgesics, antibiotics or a combination thereof. Moreover, in this specific embodiment, the drug-containing multilayer film of the present disclosure has the effect of continuously releasing the drug.

In addition, in one embodiment, the drug-containing layer of the drug-containing multilayer film of the present disclosure may have at least one microstructure protruding from the other surface thereof, and the other surface of the drug-containing layer described herein is Located on the opposite side of the anti-sticking layer.

The above-mentioned microstructure may have an upper surface. The shape of the upper surface can be arc-shaped, flat-plate, etc., but is not limited to this. The microstructures described here do not include cones or needles.

In addition, the ratio of the height of the microstructure to the width of the bottom surface 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 above-mentioned drug-containing layer has a plurality of microstructures. In this embodiment, in the plurality of microstructures, the center-to-center distance of two adjacent microstructures may be about 50-2,000 μm, for example, about 75 μm, about 100 μm, about 150 μm, or 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., but not limited thereto.

Furthermore, in the above embodiment where the drug-containing layer has a plurality of microstructures, the density of the microstructures on the drug-containing layer may be about 0.1-100 microstructures/cm ² , for example, about 1-30 microstructures/cm ² , About 0.01 microstructure/cm ² , about 0.25 microstructure/cm ² , about 0.5 microstructure/cm ² , about 1 microstructure/cm ² , about 2 microstructure/cm ² , about 3 microstructure/cm ² , about 4 Microstructure/cm ² , about 5 microstructures/cm ² , about 9 microstructures/cm ² , about 10 microstructures/cm ² , about 13 microstructures/cm ² , about 15 microstructures/cm ² , about 16 microstructures /cm ² , about 20 microstructures/cm ² , about 25 microstructures/cm ² , about 29 microstructures/cm ² , about 30 microstructures/cm ² , about 35 microstructures/cm ² , about 36 microstructures/cm ^2. About 49 microstructures/cm ² , about 50 microstructures/cm ² , about 60 microstructures/cm ² , about 64 microstructures/cm ² , about 65 microstructures/cm ² , about 70 microstructures/cm ² , About 75 microstructures/cm ² , about 80 microstructures/cm ² , about 81 microstructures/cm ² , about 90 microstructures/cm ² , about 100 microstructures/cm ² , but it is not limited thereto. As the density of the microstructure increases, the drug release efficiency will also increase.

In addition, in the embodiment where the drug-containing layer has a plurality of microstructures, the shape and/or manner in which the plurality of microstructures of the drug-containing layer are arranged is not particularly limited, and can be adjusted as required. For example, the shape in which the plurality of microstructures are arranged may include rectangles, circles, triangles, and irregular shapes, but is not limited thereto, or the plurality of microstructures may be uniformly or unevenly dispersed on the drug-containing layer. In a specific embodiment, the plurality of microstructures of the above-mentioned drug-containing layer are arranged in a matrix.

The thickness of the drug-containing layer of the drug-containing multilayer film of the present disclosure may be about 5-55 μm, such as about 20-25 μm, but is not limited thereto.

The anti-adhesion layer of the drug-containing multilayer film of the present disclosure can be composed of a second composition. The above-mentioned second composition may include, but is not limited to, a second polymer material.

Examples of the foregoing second polymer material may include, but are not limited to, polylactic acid, polyethylene glycol, etc., or any combination of the foregoing.

The viscosity of the polylactic acid in the above-mentioned second polymer material example may be about 1.1-3.0 dl/g, such as about 1.6-2.4 dl/g, but is not limited thereto.

In addition, 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 example of the 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 The diols can have different average molecular weights. The average molecular weight of the third polyethylene glycol may be about 100-1,000, for example, about 285-315, but not limited thereto, and the average molecular weight of the fourth polyethylene glycol may be about 4,000-10,000, for example, about 5,000 -7,000 etc., but not limited to this.

In one embodiment, in the anti-adhesion layer, the second polymer material may include polylactic acid, and the viscosity of the polylactic acid may be about 1.1-3.0 dl/g, but it is not limited thereto.

In another embodiment, in the anti-adhesion 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 1.1-3.0 dl/g, and the polyethylene glycol may be the third polyethylene glycol mentioned above, the fourth polyethylene glycol mentioned above or a combination thereof. In this embodiment, in the anti-adhesion layer, the weight ratio of polylactic acid to polyethylene glycol 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 not limited thereto.

Furthermore, 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 1.1-3.0 dl/g, and the polyethylene glycol may be the third Polyethylene glycol or the fourth polyethylene glycol described above.

In another specific embodiment, the second polymer material may include both polylactic acid and polyethylene glycol, the viscosity of the polylactic acid may be about 1.1-3.0 dl/g, and the polyethylene glycol may be the third polymer mentioned above. A combination of ethylene glycol and the fourth polyethylene glycol described above. 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 not limited to this.

The thickness of the anti-adhesion layer of the drug-containing multilayer film of the present disclosure may be about 10-60 μm, such as about 25-30 μm, but is not limited thereto.

Furthermore, in one embodiment, the drug-containing multilayer film of the present disclosure may further include a protective layer on the other surface of the drug-containing layer in addition to the above-mentioned drug-containing layer and the anti-adhesion layer, wherein the drug-containing layer The layer is located between the anti-sticking layer and the protective layer.

The protective layer may be composed of a third composition. The above-mentioned third composition may include a third polymer material, but is not limited thereto.

Examples of the foregoing third polymer material may include, but are not limited to, polylactic acid, polyethylene glycol, etc., or any combination of the foregoing.

The polylactic acid in the example of the third polymer material mentioned above may include polylactic acid with different viscosities and any combination thereof. For example, the polylactic acid in the example of the third polymer material 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 about 0.05-1 dl/g, such as about 0.4-0.6 dl/g, but not limited to this, and the viscosity of the fourth polylactic acid may be about 1.1-3.0 dl/g, such as about 1.6-2.4 dl/g, but not limited to this.

In addition, the polyethylene glycol in the example of the third polymer material may include polyethylene glycols of different average molecular weights and any combination thereof. For example, the polyethylene glycol in the above example of the third polymer material may include a fifth polyethylene glycol, a sixth polyethylene glycol or a combination thereof, wherein the fifth polyethylene glycol and the sixth polyethylene glycol The diols can have different average molecular weights. The average molecular weight of the fifth polyethylene glycol may be about 100-1,000, such as about 285-315, but not limited thereto, and the average molecular weight of the sixth polyethylene glycol may be about 4,000-10,000, such as about 5,000-7,000 Etc., but not limited to this.

In one embodiment, in the above-mentioned 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 above-mentioned third polylactic acid or the fourth polylactic acid, and the polyethylene glycol may be the above-mentioned fifth polylactic acid, the above-mentioned sixth polylactic acid, or a combination thereof. In this embodiment, in the above-mentioned protective layer, the weight ratio of polylactic acid to polyethylene glycol may be about 1:0.05-1, for example, 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., but not limited thereto.

Furthermore, in a specific embodiment, the third polymer material may include both polylactic acid and polyethylene glycol, and 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 polymer material may include both polylactic acid and polyethylene glycol, and the polylactic acid may be the above-mentioned third polylactic acid or the above-mentioned fourth polylactic acid, and the polyethylene glycol may be the above-mentioned A combination of the fifth polyethylene glycol and the sixth polyethylene glycol described above. 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 not limited to this.

The thickness of the anti-adhesion layer of the drug-containing multilayer film of the present disclosure may be about 1-20 μm, such as about 1-13 μm, but is not limited thereto.

In one embodiment, the drug-containing multilayer film of the present disclosure has a drug-containing layer and an anti-adhesion 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 drug-containing multilayer film of the present disclosure has a drug-containing layer and an anti-adhesion layer, and the thickness 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 drug-containing multilayer film, which can be used to form the above-mentioned drug-containing multilayer film of the present disclosure.

The method for forming the drug-containing multilayer film of the present disclosure may include, but is not limited to, the following methods (a) or method (b).

See Figure 1. Fig. 1 shows an embodiment of the method for forming the drug-containing multilayer film of the present disclosure, such as method (a).

The method (a) may include the following steps, but is not limited thereto.

First, a first solution is dried to form a film to form a drug-containing layer 101. The drug-containing layer contains the drug D, and has a surface S1 and another surface S2.

Then, a second solution is dried to form a film on the surface S1 of the above-mentioned drug-containing layer 101 to form an anti-adhesion layer 103, and the preparation of the drug-containing multilayer film 100 of an embodiment of the present disclosure is completed.

Also, see Figure 2. Figure 2 shows another embodiment of the method for forming the drug-containing multilayer film of the present disclosure, such as method (b).

The method (b) may include the following steps, but is not limited to this.

First, a second solution is dried to form a film to form an anti-adhesion layer 103.

Then, a first solution is dried to form a film on the anti-adhesion layer 103 to form a drug-containing layer 101, and the preparation of the drug-containing multilayer film 100 of an embodiment of the present disclosure is completed. The medicine D is contained in the medicine-containing layer 101.

The solute of the first solution may include a first composition. The aforementioned first composition may include, but is not limited to, a first polymer material and a drug. In addition, examples of the solvent of the above-mentioned first solution may include, but are not limited to, dichloromethane, tetrahydrofuran, chloroform, etc., but are not limited thereto.

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. In addition, the weight ratio of the first polymer material to the drug may be about 1:0.01-0.3, for example, about 1:0.015, 1:0.02, 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25 etc., but not limited to this.

The solute of the above-mentioned second solution may include a second composition. The above-mentioned second composition may include, but is not limited to, a second polymer material. Examples of the solvent of the above-mentioned second solution may include, but are not limited to, dichloromethane, tetrahydrofuran, chloroform, and the like.

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.

The first composition, the first polymer material, and the drug involved in the first solution may be the same as the first composition, the first polymer material, and the drug-containing layer of the drug-containing multilayer film of the present disclosure described above. Drugs, therefore, all related descriptions can be found in the preceding paragraphs, the first composition of the drug-containing layer of the drug-containing multilayer film of the present disclosure, the first polymer material and the drug related descriptions, and will not be repeated here.

Similarly, the second composition and the second polymer material involved in the second solution can be respectively the same as the second composition and the first high polymer of the anti-adhesion layer of the drug-containing multilayer film of the present disclosure described above. Molecular materials, therefore, all related descriptions can be found in the previous paragraph, the second composition of the anti-adhesion layer of the drug-containing multilayer film of the present disclosure and the second polymer material, and will not be repeated here. .

Furthermore, in one embodiment, in the above method (a), the method of forming the drug-containing layer may include, but is not limited to, the following steps.

See figure 3. Pour the first solution on a plate P with at least one groove R, and dry it to form a film on the plate P with at least one groove R to form the drug-containing layer 101', and make the drug-containing layer 101' There is at least one microstructure MS protruding from the surface S2'.

In this embodiment, the anti-adhesion layer 103' is then formed on the surface S1' of the drug-containing layer 101'.

The groove of the flat plate may have an upper surface. The shape of the upper surface can be arc-shaped, flat-plate, etc., but is not limited to this. The shape of the microstructure of the above-mentioned drug-containing layer is formed corresponding to the shape of the groove of the above-mentioned flat plate.

In addition, the aspect ratio of the above-mentioned groove may be about 1:2-4, such as 1:1, 1:1.5, 1:2, etc., but is not limited to this.

In one embodiment, the above-mentioned plate has a plurality of grooves. In this embodiment, in the plurality of grooves, the distance from the center to the center of two adjacent grooves may be about 50-2,000 μm, for example, about 75 μm, about 100 μm, about 150 μm, or about 200 μm. 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., but not limited thereto.

Furthermore, in the embodiment where the flat plate has a plurality of grooves, the density of the plurality of grooves may be about 0.1-100 grooves/cm ² , for example, about 1-30 grooves/cm ² , about 0.01 grooves /cm ² , about 0.25 grooves/cm ² , about 0.5 grooves/cm ² , about 1 groove/cm ² , about 2 grooves/cm ² , about 3 grooves/cm ² , about 4 grooves/cm ^2. About 5 grooves/cm ² , about 9 grooves/cm ² , about 10 grooves/cm ² , about 13 grooves/cm ² , about 15 grooves/cm ² , about 16 grooves/cm ² , About 20 grooves/cm ² , about 25 grooves/cm ² , about 29 grooves/cm ² , about 30 grooves/cm ² , about 35 grooves/cm ² , about 36 grooves/cm ² , about 49 Grooves/cm ² , about 50 grooves/cm ² , about 60 grooves/cm ² , about 64 grooves/cm ² , about 65 grooves/cm ² , about 70 grooves/cm ² , about 75 grooves /cm ² , about 80 grooves/cm ² , about 81 grooves/cm ² , about 90 grooves/cm ² , about 100 grooves/cm ² , but not limited to this.

In addition, in the embodiment where the flat plate has a plurality of grooves, the shape and/or manner of the plurality of grooves of the flat plate are not particularly limited, and can be adjusted as required. For example, the shape in which the plurality of grooves are arranged may include rectangles, circles, triangles, and irregular shapes, but is not limited thereto, or the plurality of grooves may be uniformly or unevenly distributed on the flat plate. In a specific embodiment, the plurality of grooves of the above-mentioned plate are arranged in a matrix.

In addition, 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 corroded by the second solution, and the formed film can be peeled from it without damaging the film. Examples of the material of the above-mentioned flat plate may include, but are not limited to, stainless steel, glass, Teflon, etc.

Regarding the microstructure of the drug-containing layer formed by the groove of the corresponding flat plate described here, it can be the same as the microstructure of the drug-containing layer of the drug-containing multilayer film of the present disclosure described above. Therefore, all relevant descriptions can be Please refer to the relevant description of the microstructure of the drug-containing layer of the drug-containing multilayer film of the present disclosure in the preceding paragraph, and will not be repeated here.

Also, see Figure 4. In an embodiment of the method for forming a drug-containing multilayer film of the present disclosure, the above methods (a) and method (b) may further include, but are not limited to, after both the drug-containing layer 101 and the anti-adhesion layer 103 are formed A third solution is dried to form a film on the above-mentioned drug-containing layer 101 to form a protective layer 105 to form a drug-containing multilayer film 200, wherein the drug-containing layer is located between the anti-adhesion layer and the protective layer.

Also, see Figure 5. In a specific embodiment of the method for forming a drug-containing multilayer film of the present disclosure, when the formed drug-containing layer has a microstructure, after both the drug-containing layer 101' and the anti-adhesion layer 103' are formed, The third solution is dried to form a film on the microstructured surface S2' of the aforementioned drug-containing 101' with a microstructure to form a protective layer 105' to form a drug-containing multilayer film 200', wherein the drug-containing layer 101' Located between the anti-sticking layer 103' and the protective layer 105'.

The solute of the third solution may include a third component. The aforementioned third composition may include, but is not limited to, a third polymer material. Examples of the solvent of the aforementioned third solution may include, but are not limited to, dichloromethane, tetrahydrofuran, chloroform, and the like.

In addition, the content of the third polymer material in the third 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 third composition and the third polymer material involved in the third solution can be the same as the third composition and the third polymer material of the drug-containing layer of the drug-containing multilayer film of the present disclosure described above. Therefore, All relevant descriptions can be found in the preceding paragraphs, the relevant descriptions of the third composition and the third polymer material of the protective layer of the drug-containing multilayer film of the present disclosure, and will not be repeated here.

Example

A. Anti-sticking film

A-1. Preparation of anti-sticking film

Prepare each anti-adhesion film according to the formula in Table 1 below.

Table 1 Content in solution (wt%) Anti-sticking film name Poly(DL-lactide) (viscosity 1.6-2.4 dl/g) Polyethylene glycol 300 Polyethylene glycol 6000 AM 8.8 1.1 1.1 BM 9.9 1.1 - Polyethylene glycol 300: polyethylene glycol has an average molecular weight of 285-315; polyethylene glycol 6000: polyethylene glycol has an average molecular weight of 5,000-10,000; -: no addition.

First, dissolve polylactic acid and polyethylene glycol in dichloromethane and mix them uniformly to form a solution with a total polymer content of 11 wt%.

Next, pour this solution onto a glass plate, and apply it evenly on the surface of the glass plate with an automatic film doctor and coating ruler (with a graduation of 230 μm).

Afterwards, the above glass plate is placed in an exhaust cabinet to volatilize the methylene chloride to form an anti-adhesion film.

A-2. Anti-sticking test of anti-sticking film

A-2-1. Cell test

1. Method

The cells used in this experiment were L929 cells.

(1) Observation of cell appearance

First, cut the anti-sticking film (BM) into the appropriate size and place it in the hole of the 24-well plate and add the cell suspension to the hole. Then transfer the 24-well plate to a 5% CO ₂ , 37˚C cell incubator for culture. After culturing for 24 hours, the appearance of the cells was photographed with a microscope. In the control group, only the cell suspension was added to the culture plate.

(2) Cell viability analysis

The cell survival rate was analyzed by MTT test.

First, cut the anti-sticking film (BM) into appropriate size and place it in the hole of the 96-well plate and add the cell suspension to the hole. Then transfer the 96-well plate to a cell culture incubator _{at 5% CO 2 and 37˚C for culture.} In the control group, only the cell suspension was added to the culture plate. The blank group is pure culture medium.

After culturing for 24 hours, remove the original culture medium in the culture dish, and then add fresh culture medium containing MTT reagent to the culture dish. Then place the culture plate in a cell incubator at 37˚C under _{5% CO 2 for 4 hours.}

Finally, remove the culture medium in the culture plate and add a mixture of HCl/iso-propanol to dissolve the products in the cells, and analyze the absorbance of each hole at a wavelength of 570 nm with a microplate reader.

2. Results

(1) Observation of cell appearance

The results are shown in Figure 6A.

Figure 6A shows that in the control group that only used the culture plate for culture, the cells adhered to the culture plate and grew, while in the experimental group where the anti-adhesion film was present in the culture plate, the cells could hardly adhere to the anti-adhesion film. Stick to the film, but can only be suspended in the culture medium. This result shows that the anti-adhesion layer in the present disclosure does have the effect of preventing cell adhesion and growth.

(2) Cell viability analysis

The results are shown in Figure 6B.

Figure 6B shows that the absorbance at 570nm of the control group that only uses the culture plate for culture can reach about 0.5. In contrast, the absorbance at 570nm of the experimental group with the anti-adhesion film is approximately equal to the absorbance of the pure culture medium at 570nm. Value, and this means that the cells in the experimental group can hardly survive. This test also confirms that the anti-adhesion layer in the present disclosure can prevent cell adhesion and growth.

A-2-2. Animal test

1. Method

Sprague-Dawley male rats were used for anti-adhesion test.

First, the rats were anesthetized by intraperitoneal injection of Zotetil (25 mg/0.5 ml/kg) and Xylazine (10 mg/0.5 ml/kg).

Then, an operation was performed on the right abdomen of the rat to cut an ^{opening with a size of 1.5 cm 2} and make a small scratch on the abdominal wall of the cecum and adjacent cecum (see the left photo in Figure 7).

After that, the rats were divided into three groups, which were control group, experimental group 1 and experimental group 2, and each group used 10 rats. In the control group, the rats were not implanted with any membrane. In experimental group 1, the rats were implanted with the anti-adhesion film AM prepared in the front, and in the experimental group 2, the rats were implanted with the anti-adhesion film BM prepared in the front. In the experimental group 1 and the experimental group 2, the film was implanted between the cecum and the abdominal wall of the rat (see the photo on the right in Figure 7). After the operation is completed, the cecum and abdominal wall of the rat are sutured.

After the operated rats were kept for one month, the rats were anesthetized to take pictures of the cecum and abdominal wall of the operation site and observe the degree of adhesion. Then, according to the standards shown in Table 2 below, the severity of the adhesion between the cecum and the abdominal wall of each group of rats was judged and analyzed.

Table 2. Adhesion severity based on the ratio of adhesion grade to the surface area of the damaged cecum (Shmuel Avital. et al., Dis Colon Rectum, 48: 153–157, 2005) severity grade % Has a sticky area Does not exist (absent) 0 0 Mild 1 1-100 Moderate 2 1-100 3 >100 Severe 3 100 0=No sticking; 1=Thin, silky sticky, easy to be separated; 2=Thick sticking, difficult to cut, and will not tear the organ when separated; 3=Thick sticking, unable to cut, It tears organs when separated. "Absence of adhesion" is defined as the complete absence of adhesion from the cecum to the wall of the abdominal cavity. "Mild adhesion" is defined as all grade 1 adhesions between the cecum and the wall of the abdominal cavity. "Moderate adhesion" includes all grade 2 adhesions between the cecum and the wall of the abdominal cavity and any grade 3 adhesion involving less than 100% of the adhesion area of the worn wall of the cecum. "Severe adhesion" is any grade 3 adhesion with 100% adhesion area on the worn wall of the cecum.

2. Results

The results are shown in Figure 8A and Figure 8B.

Figure 8A shows that the cecum and abdominal wall of the rats in the control group have heavy adhesion, and the rats in the experimental group 1 (anti-adhesion film AM) have only a small amount of filamentous adhesion between the cecum and the abdominal wall. In experimental group 2 (anti-adhesion film BM), there was only slight adhesion between the cecum and the abdominal cavity. Specifically, compared with rats in the control group, there are many connective tissues connected between the cecum and the abdominal cavity wall, and there is a serious adhesion situation. The rats in the experimental group 1 and the experimental group 2 have the present disclosure. The anti-adhesion film acts as a barrier, and connective tissue is not easy to form between the cecum and the abdominal wall, so the degree of adhesion is not obvious.

Figure 8B shows the percentage of rats with mild adhesion and moderate or severe adhesion in each group. Figure 8B shows that in the control group, 80% of the rats were moderately or severely adherent, and only 15% of the experimental group 1 (AM) rats were moderately adherent of grade 2 to 3. All rats were grade 1 mild adhesion, and even all rats in experimental group 2 (BM) were grade 1 moderate adhesion.

From the above results, it can be seen that the film formed by polylactic acid with high viscosity (viscosity 1.6-2.4 dl/g) can indeed achieve the anti-sticking effect.

B. Drug-containing multilayer film

B-1. Preparation of drug-containing multilayer film

B-1-1. Preparation of drug-containing multilayer film (medicine-containing layer with a flat surface)

(a) Preparation method 1

Prepare each drug-containing multilayer film according to the formula in Table 3 below.

table 3 name Content in solution (wt%) The polylactic acid poly (DL-lactide) (viscosity of 0.4-0.6 dl / g) The polylactic acid poly (DL-lactide) (viscosity of 1.6-2.4 dl / g) Polyethylene glycol 300 Polyethylene glycol 6000 Lidocaine hydrochloride M-01 Anti-sticking layer - 11 - - - Medicated layer 20 - - - 4 M-02 Anti-sticking layer - 11 - - - Medicated layer 14 - 6 - 4 M-03 Anti-sticking layer - 11 - - - Medicated layer 14 - - 6 4 M-04 Anti-sticking layer - 11 - - - Medicated layer 14 - 5 1 4 M-05 Anti-sticking layer - 11 - - - Medicated layer 14 - 3 3 4 M-06 Anti-sticking layer - 11 - - - Medicated layer 14 - 1 5 4 M-07 Anti-sticking layer - 11 - - - Medicated layer 14 - 6 - 4 The protective layer 20 - - - - M-08 Anti-sticking layer - 11 - - - Medicated layer 14 - 6 - 4 The protective layer 14 - 6 - - M-09 Anti-sticking layer - 11 - - - Medicated layer 14 - 6 - 4 The protective layer 14 - - 6 - M-10 Anti-sticking layer - 11 - - - Medicated layer 14 - 6 - 4- The protective layer 14 - 3 3 - M-11 Anti-sticking layer - 11 - - - Medicated layer - 14 3 3 4 M-12 Anti-sticking layer - 11 - - - Medicated layer - 14 3 3 4 The protective layer - 14 3 3 -

(1) Preparation of anti-adhesion layer

First, dissolve polylactic acid in dichloromethane and mix homogeneously to form a solution with a total polymer content of 11 wt%.

Next, pour this solution onto a glass plate, and apply it evenly on the surface of the glass plate with an automatic film doctor and coating ruler (with a graduation of 230 μm).

Afterwards, the above glass plate is placed in an exhaust cabinet to volatilize the methylene chloride to form an anti-adhesion layer.

(2) Preparation of drug-containing layer

The polylactic acid is dissolved in dichloromethane and mixed uniformly to form a polylactic acid solution.

If the ingredients do not contain polyethylene glycol, add lidocaine hydrochloride to the polylactic acid solution and mix uniformly to form a mixed solution. If the ingredients contain polyethylene glycol, first add polyethylene glycol to the above-mentioned polylactic acid solution and mix well, and then add lidocaine hydrochloride to this polylactic acid and polyethylene glycol solution and mix well to form a mixture Solution. In the mixed solution, the total polymer content is 20 wt%, and the drug content is 20% of the polymer content.

Next, pour the mixed solution on the surface of the anti-adhesion layer formed on the glass plate as described above, and apply it evenly on the anti-adhesion layer with an automatic doctor and a coating ruler (with a scale of 200 μm) superior.

Afterwards, the above glass plate is placed in an exhaust cabinet to volatilize the methylene chloride to form a drug-containing layer on the anti-adhesion layer. If the drug-containing multilayer film does not have a protective layer, the preparation of the drug-containing multilayer film is completed in this step. If the medicated multilayer film has a protective layer, continue the following procedure.

(3) Protective layer

The polylactic acid is dissolved in dichloromethane and mixed uniformly to form a polylactic acid solution.

If the ingredients do not contain polyethylene glycol, pour the polylactic acid solution on the drug-containing layer of the anti-adhesion layer and the drug-containing layer on the glass plate, and use an automatic film scraper and a coating ruler (The scale is 100 μm) Coat it evenly on the surface of the drug-containing layer.

If the ingredients contain polyethylene glycol, the polyethylene glycol is added to the above-mentioned polylactic acid solution and mixed uniformly to form a mixed solution, wherein the total polymer content in the mixed solution is 20 wt%. Then, pour the mixed solution onto the drug-containing layer of the two layers of the anti-adhesion layer and the drug-containing layer on the glass plate, and apply it uniformly with an automatic film scraper and a coating ruler (100 μm scale). Distributed on the surface of the drug-containing layer.

Then, the above-mentioned glass plate is placed in an exhaust cabinet to volatilize the methylene chloride 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

Prepare each drug-containing multilayer film RM according to the formula in Table 4 below.

Table 4 name Content in solution (wt%) The polylactic acid poly (DL-lactide) (viscosity of 0.4-0.6 dl / g) The polylactic acid poly (DL-lactide) (viscosity of 1.6-2.4 dl / g) Polyethylene glycol 300 Polyethylene glycol 6000 Lidocaine hydrochloride RM Medicated layer - 14 3 3 4 Anti-sticking layer - 11 - - -

(1) Preparation of drug-containing layer

First, dissolve polylactic acid in dichloromethane and mix homogeneously to form a polylactic acid solution.

Polyethylene glycol is added to the polylactic acid solution and mixed uniformly, and then lidocaine hydrochloride is added to the polylactic acid and polyethylene glycol solution and mixed uniformly to form a mixed solution. In the mixed solution, the total polymer content is 20 wt%, and the drug content is 20% of the polymer content.

Next, pour the mixed solution on a glass plate, and apply it evenly on the surface of the glass plate with an automatic film doctor and a coating ruler (with a scale of 200 μm).

Afterwards, the above glass plate is placed in an exhaust cabinet to volatilize the methylene chloride to form a drug-containing layer.

(2) Preparation of anti-adhesion layer

The polylactic acid was dissolved in dichloromethane and mixed uniformly to form a solution with a total polymer content of 11 wt%.

Then, pour the solution onto the above-mentioned drug-containing layer on a glass plate, and apply it uniformly on the surface of the drug-containing layer with an automatic film scraper and coating ruler (with a scale of 230 μm).

After that, the above glass plate is placed in an exhaust cabinet to volatilize the methylene chloride to form an anti-adhesion layer to complete the preparation of the drug-containing multilayer film RM.

The preparation method 2 can indeed form the drug-containing multilayer film RM, and it can be completely peeled from the glass plate, see Figure 9.

B-1-2. Preparation of drug-containing multilayer film (medicine-containing layer with microstructure)

Prepare each drug-containing multilayer film according to the formula in Table 5 below.

table 5 name Microstructure density ( microstructure /cm ₂ ) Center-to-center distance between two adjacent microstructures (μm) Content in solution (wt%) The polylactic acid poly (DL -lactide) (viscosity of 0.4-0.6 dl / g) The polylactic acid poly (DL -lactide) (viscosity of 1.6-2.4 dl / g) Polyethylene glycol 300 Polyethylene glycol 6000 Lidocaine hydrochloride MS-1 29 200 Medicated layer - 14 3 3 4 Anti-sticking layer - 11 - - - MS-2 13 350 Medicated layer - 14 3 3 4 Anti-sticking layer - 11 - - - MS-3 3 1000 Medicated layer - 14 3 3 4 Anti-sticking layer - 11 - - - MS-1-B 29 200 Medicated layer - 14 6 - 4- Anti-sticking layer - 11 - - - The protective layer - 14 3 3 - MS-2-B 13 350 Medicated layer - 14 6 - 4- Anti-sticking layer - 11 - - - The protective layer - 14 3 3 -

(1) Preparation of drug-containing layer

(i) Production of stainless steel molds

The surface of the stainless steel plate is processed to produce at least one groove on one surface. The number of grooves, the shape of the grooves, and the shape in which the plurality of grooves can be arranged can be set according to needs. Therefore, the specifications of the mold can be customized, and a film with a specific microstructure can be produced by turning the mold.

In this preparation, 3 stainless steel plate molds were produced. The grooves on the surface were all grooves with an arc-curved upper surface, and the groove density was 29 grooves/cm ² and 13 grooves/cm. ² and 3 grooves/cm ² .

(ii) Preparation of drug-containing layer

The polylactic acid is dissolved in dichloromethane and mixed uniformly to form a polylactic acid solution.

Polyethylene glycol is added to the polylactic acid solution and mixed uniformly, and then lidocaine hydrochloride is added to the polylactic acid and polyethylene glycol solution and mixed uniformly to form a mixed solution. In the mixed solution, the total polymer content is 20 wt%, and the drug content is 20% of the polymer content.

Then, pour the mixed solution on the above-mentioned stainless steel plate mold, and evenly coat it on the stainless steel plate mold with an automatic film doctor and a coating ruler (with a scale of 200 μm).

Afterwards, the above-mentioned stainless steel plate mold is placed in an exhaust cabinet to volatilize the methylene chloride (about 24 hours) to form a micro-structured drug-containing layer.

(2) Preparation of anti-adhesion layer

The polylactic acid was dissolved in dichloromethane and mixed uniformly to form a solution with a polymer content of 11 wt%.

Then, pour the solution on the above-mentioned drug-containing layer on a stainless steel plate mold, and evenly coat it on the surface of the drug-containing layer with an automatic film scraper and a coating ruler (with a scale of 230 μm).

Afterwards, the aforementioned stainless steel plate is placed in an exhaust cabinet to volatilize the methylene chloride to form an anti-adhesion layer. If the drug-containing multilayer film does not have a protective layer, the preparation of the drug-containing multilayer film is completed in this step. If the medicated multilayer film has a protective layer, continue the following procedure.

(3) Protective layer

The polylactic acid and polyethylene glycol are dissolved in dichloromethane and mixed uniformly to form a mixed solution. In the mixed solution, the total polymer content is 20 wt%.

Next, remove the two-layer film of the drug-containing layer and the anti-adhesion layer on the stainless steel plate from the stainless steel plate mold, and make the two-layer film of the drug-containing layer and the anti-adhesion layer face up with the microstructure of the drug-containing layer Place on the surface of a glass plate.

Pour the mixed solution on the micro-structured surface of the two-layer film of the drug-containing layer and the anti-adhesion layer, and apply it evenly on the surface of the drug-containing layer with an automatic film scraper and a coating ruler (scale of 100 μm) .

Then, the above glass plate is placed in an exhaust cabinet to volatilize the methylene chloride 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 of drug-containing multilayer films

1. Method

The medicated multilayer film is cut into an appropriate size and placed in a tissue embedding box to fix the film around the film to avoid curling of the film.

Then place the above-mentioned tissue embedding cassette in a glass bottle containing 40 ml of phosphate buffered saline (PBS), and shake the glass bottle at a speed of 100 rpm so that the film can simulate the dynamic environment of the body The drug will be released at a specific time point and sample will be taken.

The release test is divided into immediate release test and sustained release test. The sampling time of immediate release type is 0.5, 1, 2, 4, 6, 8 and 24 hours, while the sampling time of continuous release test is 0.5, 1, 2, 4, 6, 8, 24, 48, 96, 168, 264 and 336 hours.

Draw 4 ml of PBS from the glass bottle for each sampling, and then add the same volume of fresh PBS to maintain the total volume of PBS at 40 ml. The sampled PBS was diluted and analyzed with an enzyme immunoassay analyzer (Elisa reader) to analyze the drug content, and the cumulative release of the film at each time point was confirmed by calculation.

In addition, in order to confirm the total drug content in each film, the film was cut into multiple small-sized film pieces and placed in a glass sample bottle.

Add 4 ml of PBS to the glass bottle, and ultrasonically shake the glass bottle to extract the drug in the film. The extraction time lasts about 30 minutes. After that, the drug concentration in the PBS was analyzed by high performance liquid chromatography (HPLC) to confirm the total amount of drug contained in the film.

The cumulative drug release rate (%) of the film at each time point is calculated by the following formula. The cumulative drug release rate of the film at each time point% = the cumulative release of the drug at each time point / the total drug content contained in the film * 100

2. Results

(1) Result of immediate release test of drug-containing multilayer films M-01, M-02, M-03, M-04, M-05 and M-06

The results of the immediate release test of the drug-containing multilayer films M-01, M-02, M-03, M-04, M-05 and M-06 are shown in Figure 10.

According to Figure 10, when the main component of the drug-containing layer in the drug-containing multilayer film is composed of low-viscosity polylactic acid (0.4-0.6 dl/g), regardless of whether the drug-containing layer contains polyethylene glycol (polyethylene glycol) Ethylene glycol 300, polyethylene glycol 6000 or their combination), the drug release curve of the drug-containing multilayer film all show an initial rapid release phenomenon, and the cumulative drug release rate of one hour can reach more than 40%, and The 24-hour cumulative drug release rate reached more than 80%.

The above results show that when low-viscosity polylactic acid (0.4-0.6 dl/g) is used as the main component of the drug-containing layer, the structure of the drug-containing layer is relatively loose, so the drug is easily released from the film through the diffusion mechanism. Therefore, when the drug-containing layer is composed of low-viscosity polylactic acid (0.4-0.6 dl/g), the drug-containing multilayer film is suitable as an immediate release film.

(2) Immediate release test results of the drug-containing multilayer films M-02, M-07, M-08, M-09 and M-10

In order to confirm the influence of protective layers with different components on drug release, the drug-containing multilayer film M-02 (without protective layer) and the drug-containing multilayer film M-07, M-08, M-09 and M-10 (with protection The result of the immediate release test of layer) is shown in Figure 11.

According to Figure 11, compared to the drug-containing multilayer film M-02 without a protective layer, the drug-containing multilayer film M-07, which has a protective layer composed of polylactic acid (0.4-0.6 dl/g) with low viscosity, can Reduce the cumulative release rate of the drug from 0 to 24 hours. When the composition of the protective layer contains polyethylene glycol 300 or polyethylene glycol 6000, the cumulative drug release rate of the drug-containing multilayer film does not show a decreasing trend, which means that the presence of polyethylene glycol will make the protective layer The structure is porous, and the effect of the 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 influence of the polylactic acid viscosity of the drug-containing layer in the drug-containing multilayer film and the protective layer on the drug release of the drug-containing multilayer film, the drug-containing multilayer film M-02 (without a protective layer) and the drug-containing multilayer film M-11 The results of the release test with M-12 are shown in Figure 12.

According to Figure 12, compared to the drug-containing multilayer film M-05 composed of low-viscosity polylactic acid (0.4-0.6 dl/g) as the main component of the drug-containing layer, the main component of the drug-containing layer is high-viscosity The drug-containing multi-layer film M-11 composed of polylactic acid (1.6-2.4 dl/g) has a 0-1 hour cumulative drug release rate, and its 24-hour cumulative drug release rate also increased from 85 % Reduced to 32%.

In addition, the drug-containing multilayer film (M-11 and M12) composed of high-viscosity polylactic acid (1.6-2.4 dl/g), which is the main component of the drug-containing layer, did not show significant rapid release in the initial stage. As the time lengthened, the cumulative release rate of the drug within 14 days only reached 50%, indicating that the drug-containing multilayer film can be released continuously for more than 14 days. Cumulative drug release

This result shows that when the main component of the drug-containing layer is composed of high-viscosity polylactic acid (1.6-2.4 dl/g), the structure of the drug-containing layer is relatively compact, which can prolong the release time of the drug from the film.

Therefore, when the drug-containing layer is composed of high-viscosity polylactic acid (1.6-2.4 dl/g), 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 show that compared to the drug-containing multilayer film M-11 without a protective layer, the drug-containing multilayer film M-12 with a protective layer no longer shows faster initial performance. Release (0-1 hour drug cumulative release rate), and its 14-day drug cumulative release rate is only about 40%. This shows that when the main component of the drug-containing layer is composed of high-viscosity polylactic acid (1.6-2.4 dl/g), 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 that the drug-containing layer in the drug-containing multilayer film has a microstructure on the drug release of the drug-containing multilayer film, the drug-containing multilayer film M-11 (the drug-containing layer does not have a microstructure) and the drug-containing multilayer film MS-1, The results of the MS-2 and MS-3 release tests are shown in Figure 13.

As the number of microstructures in the drug-containing layer increases, the cumulative drug release rate will increase correspondingly. The drug-containing multilayer film (MS-1) with the largest number of microstructures per unit area has a drug-containing multilayer film (MS-1) with a cumulative drug release rate of 100% in 14 days, which is compared with a drug-containing multilayer film without a microstructure ( M-11) increased the release rate by 50%.

In contrast, when the number of microstructures per unit area of the drug-containing layer decreases, the increase in the cumulative drug release rate also decreases. Compared with the drug-containing multilayer film M-11 with no microstructure in the drug-containing layer, the cumulative release rate of the drug-containing multilayer film MS-2 and MS-3 only increased by 30% and 20% in 14 days.

In addition, the results of scanning electron microscopy analysis of the drug-containing multilayer films MS-1, MS-2 and MS-3 are shown in Figure 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 influence of the protective layer on the drug release of the drug-containing multilayer film with a micro-structured drug-containing layer, the release test of the drug-containing multilayer film MS-1, MS-2, MS-1-B and MS-2-B The results are shown in Figure 15.

According to Figure 15, compared with the drug-containing multilayer film MS-1, the drug-containing multilayer film MS-1-B with a protective layer has a cumulative release rate from 100% to 50% on the 14th day. The drug-containing multilayer film MS-2, and the drug-containing multilayer film MS-2-B with a protective layer, the cumulative release rate dropped from 80% to 40% on the 14th day.

In addition, the results of scanning electron microscopy analysis of the drug-containing multilayer films MS-1-B and MS-2-B are shown in Figure 16.

It can be seen from Figure 16 that the microstructure of the drug-containing layer of the drug-containing multilayer films MS-1-B and MS-2-B has been covered by the protective layer, which greatly reduces the surface area, thus making it difficult for the drug to diffuse from the film. Out, thereby reducing the cumulative release rate of the drug.

Although the present invention has been disclosed as above in the preferred embodiment, it is not intended to limit the present invention. Anyone familiar with the art can make some changes and modifications without departing from the spirit and scope of the present invention. Therefore, the present invention The scope of protection shall be subject to the scope of the attached patent application.

100, 100’, 200, 200’: the medicine-containing multilayer film disclosed in this disclosure 101, 101’: medicinal layer 103, 103’: Anti-sticking layer 105, 105’: Protective layer S1, S1’, S2, S2’: the surface of the medicinal layer 101, 101’ D: Drugs MS: Microstructure of drug-containing layer 101’ P: Tablet R: The groove of the plate

Figure 1 shows an embodiment of the method for forming the drug-containing multilayer film of the present disclosure. Figure 2 shows another embodiment of the method for forming the drug-containing multilayer film of the present disclosure. Figure 3 shows, in one embodiment, the method for forming the drug-containing layer of the drug-containing multilayer film of the present disclosure. Figure 4 shows yet another embodiment of the method for forming the drug-containing multilayer film of the present disclosure. Figure 5 shows yet another embodiment of the method for forming the drug-containing multilayer film of the present disclosure. Figure 6A shows a photograph of the cell experiment in the anti-adhesion test of the anti-adhesion film. Figure 6B shows the cell survival analysis results of the cell test in the anti-adhesion test of the anti-adhesion film. Figure 7 shows the surgical method of the animal experiment in the anti-adhesion test of the anti-adhesion film. Figure 8A shows a photograph of the operation area of each group of rats in the animal experiment in the anti-adhesion test of the anti-adhesion film. Figure 8B shows the percentage of the number of rats with mild adhesion and moderate or severe adhesion in each group in the animal experiment in the anti-adhesion test of the anti-adhesion film. Figure 9 shows a photograph of the drug-containing multilayer film RM of the present disclosure. Figure 10 shows the results of the immediate release test of the drug-containing multilayer films M-01, M-02, M-03, M-04, M-05, and M-06 of the present disclosure. Figure 11 shows the instant release test of the drug-containing multilayer film M-02 (without protective layer) and the drug-containing multilayer film M-07, M-08, M-09 and M-10 (with protective layer) of the present disclosure result. Figure 12 shows the release test results of the drug-containing multilayer film M-05 (without a protective layer) and the drug-containing multilayer film M-11 and M-12 of the present disclosure. Figure 13 shows the release test results of the drug-containing multilayer film M-11 (the drug-containing layer does not have a microstructure) and the drug-containing multilayer film MS-1, MS-2, and MS-3 of the present disclosure. Figure 14 shows the results of scanning electron microscopy analysis of the drug-containing multilayer films MS-1, MS-2 and MS-3 of the present disclosure. Figure 15 shows the release test results of the drug-containing multilayer films MS-1, MS-2, MS-1-B and MS-2-B. Figure 16 shows the results of scanning electron microscopy analysis of drug-containing multilayer films MS-1-B and MS-2-B.

100: The medicated multilayer film disclosed in this disclosure

101: medicated layer

103: Anti-sticking layer

S1, S2: The surface of the drug-containing layer 101

D: Drugs

Claims (32)

A medicine-containing multilayer film, including: A medicated layer; and An anti-adhesion layer, the anti-adhesion layer on a surface of the drug-containing layer, The drug-containing layer is composed of a first composition, the first composition includes a first polymer material and a drug, and the first polymer material includes 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 1:0.01-0.3, The anti-adhesion layer is composed of a second composition, the second composition includes a second polymer material, and the second polymer material includes at least one selected from the group consisting of: Polylactic acid and polyethylene glycol. The drug-containing multilayer film according to claim 1, wherein the first polymer material includes the polylactic acid, and the polylactic acid is a first polylactic acid or a second polylactic acid, wherein the first polylactic acid The viscosity of the second polylactic acid is 0.05-1 dl/g, and the viscosity of the second polylactic acid is 1.1-3.0 dl/g. The drug-containing multilayer film as described in item 2 of the scope of patent application, wherein the first polymer material is the polylactic acid, and the polylactic acid is the first polylactic acid, and the drug includes: Analgesics, anti-inflammatory analgesics, or combinations thereof. The drug-containing multilayer film according to the second item of the scope of patent application, wherein the first polymer material is the polylactic acid, and the polylactic acid is the second polylactic acid, and the drug includes: Analgesics, antibiotics, or combinations thereof. The drug-containing multi-layer film according to claim 1, wherein the first polymer material includes the polylactic acid and the polyethylene glycol, and the polylactic acid is a first polylactic acid or a second polylactic acid, And the polyethylene glycol is a first polyethylene glycol, a second polyethylene glycol or a combination thereof, wherein the viscosity of the first polylactic acid is 0.05-1 dl/g, and the viscosity of the second polylactic acid It is 1.1-3.0 dl/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. The drug-containing multilayer film described in item 5 of the scope of patent application, wherein in the first polymer material, the weight ratio of the polylactic acid to the polyethylene glycol is 1:0.05-1. The drug-containing multilayer film as described in item 5 of the scope of patent application, wherein the first polymer material is a combination of the polylactic acid and the polyethylene glycol, and the polylactic acid is a first polylactic acid or a second polylactic acid Lactic acid, and the polyethylene glycol is the first polyethylene glycol or the second polyethylene glycol. The drug-containing multilayer film according to item 7 of the scope of patent application, wherein the polylactic acid is the first polylactic acid, and the drug includes: Analgesics, anti-inflammatory analgesics, or combinations thereof. The drug-containing multilayer film according to item 7 of the scope of patent application, wherein the polylactic acid is the second polylactic acid, and the drug includes: Analgesics, antibiotics, or combinations thereof. The drug-containing multi-layer film according to claim 5, wherein the first polymer material is a combination of the polylactic acid and the polyethylene glycol, and the polylactic acid is the first polylactic acid or the second polylactic acid Lactic 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. The drug-containing multilayer film according to claim 10, wherein the polylactic acid is the first polylactic acid, and the drug includes: Analgesics, anti-inflammatory analgesics, or combinations thereof. The drug-containing multilayer film according to claim 10, wherein the polylactic acid is the second polylactic acid, and the drug includes: Analgesics, antibiotics, or combinations thereof. The drug-containing multilayer film as described in item 1 of the scope of patent application, wherein the drug-containing layer has a plurality of microstructures protruding from the other surface thereof. The drug-containing multilayer film as described in item 13 of the scope of the patent application, wherein the microstructure has an upper surface, and the shape of the upper surface includes a curved surface or a flat plate. The medicine-containing multilayer film as described in item 13 of the scope of patent application, wherein the ratio of the height of the microstructure to the width of the bottom surface is 1:2-4. The drug-containing multilayer film described in item 13 of the scope of patent application, wherein the drug-containing layer has a plurality of microstructures. The drug-containing multilayer film described in item 16 of the scope of patent application, wherein the density of the microstructure on the drug-containing layer is 0.1-100 pcs/cm ² . The drug-containing multilayer film described in item 1 of the scope of patent application, wherein the second polymer material includes the polylactic acid, and the viscosity of the polylactic acid is 1.1-3.0 dl/g. The drug-containing multilayer film described in item 1 of the scope of patent application, wherein the second polymer material includes the polylactic acid and the polyethylene glycol, and the polyethylene glycol is a third polyethylene glycol, a first Tetra polyethylene glycol or a combination thereof, wherein the viscosity of the polylactic acid is 0.05-1 dl/g, and wherein the average molecular weight of the third polyethylene glycol is 100-1,000, and the average molecular weight of the fourth polyethylene glycol is 4,000-10,000. The drug-containing multilayer film described in item 1 of the scope of patent application further includes a protective layer on the other surface of the drug-containing layer, wherein the drug-containing layer is located between the anti-adhesion layer and the protective layer, Furthermore, the protective layer is composed of a third composition, the third composition includes a third polymer material, and the third polymer material includes at least one selected from the group consisting of: Polylactic acid and polyethylene glycol. The drug-containing multilayer film according to claim 20, wherein the third polymer material includes the polylactic acid, and the polylactic acid is a third polylactic acid or a fourth polylactic acid, wherein the third polylactic acid The viscosity of the fourth polylactic acid is 0.05-1 dl/g, and the viscosity of the fourth polylactic acid is 1.1-3.0 dl/g. The drug-containing multilayer film according to claim 20, wherein the third polymer material includes 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 0.05-1 dl/g, and the viscosity of the fourth polylactic acid It is 1.1-3.0 dl/g, wherein the average molecular weight of the fifth polyethylene glycol is 100-1,000, and the average molecular weight of the sixth polyethylene glycol is 4,000-10,000. The drug-containing multilayer film according to claim 22, wherein the third polymer material is a combination of the polylactic acid and the polyethylene glycol, and the polylactic acid is a third polylactic acid or a fourth polylactic acid Lactic acid, and the polyethylene glycol is the fifth polyethylene glycol or the sixth polyethylene glycol. The drug-containing multilayer film according to claim 22, wherein the third polymer 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 Lactic 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. A method for forming a drug-containing multilayer film includes the following method (a) or method (b): Method (a), including: (i) drying a first solution into a film to form a drug-containing layer; and (ii) drying a second solution to form a film on one surface of the drug-containing layer to form an anti-adhesion layer; Method (b), including: (i’) drying a second solution into a film to form an anti-sticking layer; and (ii') drying a first solution to form a film on the anti-adhesion layer to form a drug-containing layer, The solute of the first solution includes a first polymer material and a drug, and the first polymer material includes at least one selected from the group consisting of: Polylactic acid and polyethylene glycol, And the content of the first polymer material in the first solution is 5-30 wt%, and the weight ratio of the first polymer material to the drug is 1:0.01-0.3, Furthermore, the solute of the second solution includes a second polymer material, and the second polymer material includes 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 5-30 wt%. According to the method for forming a drug-containing multilayer film described in claim 25, wherein the first polymer material includes the polylactic acid, and the polylactic acid is a first polylactic acid or a second polylactic acid, and the first polymer material is a first polylactic acid or a second polylactic acid. The viscosity of a polylactic acid is 0.05-1 dl/g, and the viscosity of the second polylactic acid is 1.1-3.0 dl/g. According to the method for forming a drug-containing multilayer film according to item 25 of the patent application, the first polymer material includes the polylactic acid and the polyethylene glycol, and the polylactic acid is a first polylactic acid or a second polylactic acid. Polylactic acid, and the polyethylene glycol is a first polyethylene glycol, a second polyethylene glycol, or a combination thereof, wherein the viscosity of the first polylactic acid is 0.05-1 dl/g, and the second polyethylene glycol The viscosity of lactic acid is 1.1-3.0 dl/g, and 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. The method for forming a drug-containing multilayer film as described in item 25 of the scope of patent application, wherein in the mode (a), the method for forming the drug-containing layer includes: Pour the first solution on a flat plate with at least one groove, and dry it to form a film on the flat plate with at least one groove, so that the drug-containing layer has at least one microstructure protruding from the other On the surface. According to the method for forming a drug-containing multilayer film described in item 28 of the scope of the patent application, the groove has an upper surface, and the shape of the upper surface includes a curved surface or a flat plate. According to the method for forming a drug-containing multilayer film described in claim 25, the second polymer material includes the polylactic acid, and the viscosity of the polylactic acid is about 1.1-3.0 dl/g. The method for forming a drug-containing multilayer film as described in item 25 of the scope of patent application, wherein the second polymer material includes 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 0.05-1 dl/g, and wherein the average molecular weight of the third polyethylene glycol is about 100-1,000, and the fourth polyethylene glycol The alcohol average molecular weight is about 4,000-10,000. The method for forming a drug-containing multilayer film as described in item 25 of the scope of patent application, wherein The method (a) and method (b) further include: (iii) drying a third solution to form a film on the drug-containing layer to form a protective layer, wherein the drug-containing layer is located between the anti-adhesion layer and the protective layer, Furthermore, the solute of the third solution includes a third polymer material, and the third polymer material includes at least one selected from the group consisting of: Polylactic acid and polyethylene glycol, And the content of the third polymer material in the third solution is about 5-30 wt%.

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