Rod core, punching type implant, preparation method and application

Abstract

The invention discloses a rod core, a punching type implant as well as a preparation method and application of the punching type implant. The rod core comprises a drug-containing layer, and the drug-containing layer comprises active drugs and auxiliary materials. The auxiliary materials comprise sustained and controlled release auxiliary materials; the molecular weight of the sustained and controlled release auxiliary material is 10000-10000 thousands; the medicine-adjuvant ratio is 1: (0.01-100); the medicine-adjuvant ratio represents the mass ratio of the active medicine to the adjuvant in the medicine-containing layer; optionally, the rod core of the punching type implant also comprises a boosting layer compounded on the medicine-containing layer. The implant provided by the invention can be suitable for most drugs, and can realize long-acting release of the drugs.

Description

Technical Field

[0001] The invention relates to a rod core, a punched implant, a preparation method and an application thereof. Background Art

[0002] Subcutaneous implants mainly place active drugs in carriers and implant them under the skin. The implants control the release of drugs through the carriers. The drugs are absorbed into the blood circulation through local capillaries, and can achieve stable release for several years to achieve long-term effects. This preparation avoids the first-pass effect in the gastrointestinal tract, thereby greatly improving the bioavailability of the drug. Since it needs to be implanted in the body, the material selection of its carrier is particularly important.

[0003] Implants are usually composed of a drug core and a silicone tube. Traditional implant drug cores are generally divided into two types: one is a rod core filled with powdered drugs. Powdered drug filling has problems such as large drug loss, difficulty in controlling drug filling uniformity, and obvious drug release burst. The other is a silicone skeleton rod core, which requires high-temperature vulcanization and shaping during its preparation process. Obviously, this rod core is not suitable for heat-sensitive drugs that are easily degraded at high temperatures.

[0004] The silicone tube of traditional silicone implants is not perforated. The silicone tube forms pores through its own cross-linked mesh structure. External water enters the silicone tube through these pores, dissolving the drug to form a solution. The drug solution first diffuses to the silicone tube wall and adsorbs on the silicone tube wall. Since the polarity of silica gel is very small, only drugs with very small polarity can complete this adsorption process and then diffuse. Drugs with high polarity cannot diffuse to the outside of the silicone tube. Secondly, due to the properties of silica gel itself and the size of the silicone tube's own mesh pores, only small molecule drugs with low polarity and less than 800 molecular weight and water molecules can pass through, and it has a significant interception effect on drugs with a molecular weight greater than 800, so it is not applicable to large molecule drugs.

[0005] Therefore, in order to solve the above problems, it is urgent to develop an implant suitable for various types of drugs. Summary of the invention

[0006] The technical problem to be solved by the present invention is to overcome the defects of the implant in the prior art that the application scope is narrow, especially the lack of application to drugs with high solubility, heat-sensitive drugs or macromolecular drugs, and provide a rod core, perforated implant and preparation method and application. The implant of the present invention can be applied to most drugs and can achieve long-term release of drugs.

[0007] In the present invention, the inventors, after a large number of experimental studies, use a solid column pressing method to compress and mold active drugs and excipients to obtain a rod core, which not only solves the problem of drug waste or unstable drug release in powder-type drug cores, but also solves the problem of unstable drugs in the preparation process of silicone skeleton-type rod cores. After the silicone tube is punched, the release amount of the drug is increased, and the application range of the implant is expanded.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The present invention provides a rod core for a perforated implant, which comprises a drug-containing layer, wherein the drug-containing layer comprises an active drug and excipients;

[0010] Wherein, the excipients include sustained-release excipients; the molecular weight of the sustained-release excipients is 10-10 million;

[0011] The drug-excipient ratio is 1:(0.01-100); the drug-excipient ratio represents the mass ratio of the active drug to the excipient in the drug-containing layer;

[0012] Optionally, the rod core of the perforated implant further includes a boosting layer composited on the drug-containing layer.

[0013] In the present invention, the active drug may include conventional drugs in the art, for example, one or more of macromolecular drugs with good solubility, small molecule drugs with good solubility, macromolecular drugs with poor solubility, and small molecule drugs with poor solubility.

[0014] Among them, the macromolecular drug with good solubility can be a conventional active drug in the art with a drug solubility of >10 mg / mL and a drug molecular weight greater than 800 Da, preferably including an active drug with a drug solubility of >30 mg / mL and a drug molecular weight greater than 800 Da, such as one or more of exenatide, semaglutide, Centella asiatica glycosides and human growth hormone.

[0015] Among them, the small molecule drug with good solubility can be a conventional active drug in the art with a drug solubility of >10 mg / mL and a drug molecular weight of less than or equal to 800 Da, preferably including an active drug with a drug solubility of >30 mg / mL and a drug molecular weight of less than or equal to 800 Da, such as metformin and / or doxorubicin hydrochloride.

[0016] Among them, the macromolecular drug with poor solubility can be a conventional active drug in the art with a drug solubility of ≤10 mg / mL and a drug molecular weight greater than 800 Da, preferably including an active drug with a drug solubility of ≤5 mg / mL and a drug molecular weight greater than 800 Da, such as one or more of bovine insulin, paclitaxel and levothyroxine sodium.

[0017] Among them, the small molecule drug with poor solubility can be a conventional active drug in the art with a drug solubility of ≤10 mg / mL and a drug molecular weight of less than or equal to 800 Da, preferably including an active drug with a drug solubility of ≤5 mg / mL and a drug molecular weight of less than or equal to 800 Da, such as one or more of estradiol, gestodene, levonorgestrel, meloxicam, ganciclovir, puerarin and paliperidone.

[0018] In the present invention, the weight average molecular weight of the sustained-release excipient is preferably 11 million to 8 million, for example, 11.71 million, 10,000, 44,000, 200,000, 300,000, 400,000 or 7 million.

[0019] In the present invention, the sustained-release excipient preferably includes a poorly soluble skeleton material and / or a hydrophilic gel material.

[0020] Wherein, the weight average molecular weight of the poorly soluble skeleton material is preferably 20 million to 8 million, preferably 30 million to 7 million;

[0021] The poorly soluble skeleton material preferably includes one or more of calcium alginate, methyl cellulose, polyethylene, polyvinyl chloride, methacrylic acid-methyl acrylate copolymer and ethyl cellulose, such as ethyl cellulose. The methacrylic acid-methyl acrylate copolymer is preferably one or more of Eudragit S100, Eudragit L100, RL, RS, NE and FS, such as Eudragit S100.

[0022] The weight average molecular weight of the hydrophilic gel material may be 1,000-8,000,000, preferably 10,000-7,000,000.

[0023] Wherein, the hydrophilic gel material preferably includes one or more of hydroxypropyl methylcellulose, polyethylene oxide, sodium alginate, chitosan, agar, xanthan gum, carbomer, polyvinyl alcohol, N-vinyl amide polymer, polylactic acid-glycolic acid copolymer (PLGA) and polyethylene oxide. The hydroxypropyl methylcellulose is preferably one or more of HPMC K100M, HPMC K15M and HPMC K4M. The N-vinyl amide polymer is preferably PVP K30 and / or PVP K90. The polyethylene oxide is preferably one or more of PEO N80, PEO N-750, PEO WSR N-12K, PEO WSR N-60K, PEO WSR303 and PEO WSR 1105.

[0024] Among them, when the sustained-release excipients are poorly soluble skeleton materials and hydrophilic hydrogel materials, the mass ratio of the poorly soluble skeleton materials and the hydrophilic hydrogel materials is preferably 1:(0.01-100), for example, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60, 1:80 or 1:100.

[0025] In a preferred embodiment, the active drug is insulin, and the excipients are the sustained-release excipient and the drug stabilizer, such as HPMC K4M and trehalose. The mass ratio of the sustained-release excipient to the excipient can be 1:4.33.

[0026] In a preferred embodiment, the active drug is semaglutide, and the excipients are the sustained-release excipient and the filler, such as HPMC K4M and MCC. The mass ratio of the sustained-release excipient to the excipient can be 1:4.33.

[0027] In a preferred embodiment, the active drug is metformin, and the excipients are the sustained-release excipient and the filler, such as HPMC K4M and MCC. The mass ratio of the sustained-release excipient to the excipient can be 1:4.33.

[0028] In a preferred embodiment, the active drug is paliperidone, and the excipients are the sustained-release excipient and the filler, such as HPMC K4M and MCC. The mass ratio of the sustained-release excipient to the excipient can be 1:4.33.

[0029] In a preferred embodiment, the active drug is exenatide, and the excipient is the sustained-release excipient, which is preferably one or more of Eudragit S100, calcium alginate, ethyl cellulose, PLGA, HPMCK 15M and PEO N80, such as ethyl cellulose, or ethyl cellulose and HPMCK 15M.

[0030] In a preferred embodiment, the active drug is metformin, and the excipient is the sustained-release excipient, which preferably includes one or more of ethyl cellulose, HPMCK 15M, HPMCK 4M and PEO N80, such as HPMCK 15M, HPMCK 4M, or ethyl cellulose and HPMCK 15M.

[0031] In a preferred embodiment, the active drug is semaglutide, and the sustained-release excipient preferably includes one or more of Eudragit S100, calcium alginate, ethyl cellulose, PLGA, HPMCK 15M and PEO N80, such as ethyl cellulose, or ethyl cellulose and HPMCK 15M.

[0032] In a preferred embodiment, the active drug is levothyroxine sodium, and the excipients preferably include the sustained-release excipients and the filler, such as PEO N-750 and MCC.

[0033] In the present invention, the excipient ratio is preferably 1:(0.01-99), for example 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60 or 1:80.

[0034] In the present invention, the excipients preferably also include one or more of a drug stabilizer, a filler and a suspending agent.

[0035] Wherein, the drug stabilizer is preferably trehalose.

[0036] Wherein, the filler is preferably one or more of starch, dextrin, microcrystalline cellulose (MCC) and lactose.

[0037] Wherein, the suspending agent is preferably hydroxypropyl methylcellulose and / or polyethylene oxide.

[0038] Among them, the mass ratio of the sustained-release excipient to the excipient is preferably 1:(0.01-100), for example 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60, 1:80 or 1:100.

[0039] In the present invention, the concentration of the active drug in the drug-containing layer can be set as a gradient concentration. The gradient is preferably 1-50 segments, such as 2 segments, 3 segments, 5 segments, 10 segments, 20 segments, or 40 segments; the gradient concentration is generally expressed as the concentration of each gradient is independent.

[0040] Wherein, when the gradient is 3 sections, the gradient is preferably set to the first gradient drug release module, the second gradient drug release module and the third gradient drug release module in sequence, and the concentration of the active drug in the first gradient drug release module is preferably 0.1%-50%, such as 2%, 5% or 10%. The concentration of the active drug in the second gradient drug release module is preferably 1%-80%, such as 10% or 20%. The concentration of the active drug in the third gradient drug release module is preferably 1%-100%, such as 20% or 30%. The concentration of the active drug generally indicates the percentage of the mass of the active drug to the mass of the gradient drug release module.

[0041] In a preferred embodiment, the concentration of the active drug in the drug-containing layer is set to three stages, the concentration of the active drug in the first gradient drug release module is 2%, the concentration of the active drug in the second gradient drug release module is 10%, and the concentration of the active drug in the third gradient drug release module is preferably 20%.

[0042] In a preferred embodiment, the concentration of the active drug in the drug-containing layer is set to three stages, the concentration of the active drug in the first gradient drug release module is 2%, the concentration of the active drug in the second gradient drug release module is 20%, and the concentration of the active drug in the third gradient drug release module is preferably 30%.

[0043] In a preferred embodiment, the concentration of the active drug in the drug-containing layer is set to three stages, the concentration of the active drug in the first gradient drug release module is 10%, the concentration of the active drug in the second gradient drug release module is 20%, and the concentration of the active drug in the third gradient drug release module is preferably 30%.

[0044] In a preferred embodiment, the concentration of the active drug in the drug-containing layer is set to three stages, the concentration of the active drug in the first gradient drug release module is 5%, the concentration of the active drug in the second gradient drug release module is 20%, and the concentration of the active drug in the third gradient drug release module is preferably 30%.

[0045] In the present invention, when the stick core further comprises a boosting layer, the raw material of the boosting layer preferably comprises an expansion material and a permeation promoter.

[0046] The expansion material in the boosting layer may be polyethylene oxide, preferably polyethylene oxide with a weight average molecular weight of 100,000-700,000, such as one or more of PEO N-80, PEO N-750, PEO WSR 1105, PEO WSR 303, PEO N-12K and PEO N-60K.

[0047] The permeation enhancer in the boosting layer may be a conventional substance in the art capable of increasing osmotic pressure, preferably one or more of mannitol, lactose, fructose, glucose and NaCl, such as NaCl.

[0048] Among them, the mass ratio of the expansion material and the permeation promoter in the boost layer is preferably (0.01-100):1, for example, 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1 or 100:1.

[0049] In the present invention, when the stick core further includes a boost layer, the mass ratio of the drug-containing layer to the boost layer may be (0.01-100):1, for example, 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1 or 100:1.

[0050] In the present invention, when the rod core further includes a boost layer, the preparation method of the boost layer can be conventional in the art, for example, the raw material of the boost layer can be pressed.

[0051] The pressing can be performed by solid column forming. The pressing pressure can be 0.01-10 MPa.

[0052] In the present invention, when the stick core further includes a boosting layer, the number of the boosting layers may be an integer, preferably an even number, such as 2. When the number of the boosting layers is an even number, the boosting layers are preferably respectively disposed at both ends of the drug-containing layer.

[0053] In the present invention, the single pressing length of the rod core is preferably 1-50 mm, such as 1 mm or 2 mm or 3 mm or 4 mm or 5 mm or 7 mm or 10 mm or 20 mm or 30 mm or 40 mm or 50 mm. The total length of the rod core can be selected according to the length of the silicone tube.

[0054] In the present invention, the total length of the rod core is preferably 1-100 mm, more preferably 5-60 mm, such as 7 mm or 10 mm or 15 mm or 18 mm or 20 mm or 30 mm or 40 mm or 50 mm or 60 mm.

[0055] In the present invention, the diameter of the rod core is preferably 1-10 mm, more preferably 1-5 mm, such as 2 mm, 3 mm or 4 mm.

[0056] The present invention also provides a method for preparing the perforated implant rod core as described above, which comprises the following steps: compressing the active drug and the auxiliary material to obtain the drug-containing layer;

[0057] Optionally, the boosting layer is compounded on the drug-containing layer.

[0058] In the present invention, the pressing pressure is 0.01-10 MPa, such as 0.1, 0.2, 0.3, 0.5, 1, 2, 5 or 10 MPa.

[0059] In the present invention, the pressing can be accomplished by solid column pressing.

[0060] The present invention also provides a perforated implant, which comprises the stick core for the perforated implant as described above and a silicone tube with drug-releasing holes coated on the outside of the stick core.

[0061] In the present invention, when the silicone tube is wrapped around the outside of the rod core, the center point of the rod core and the center point of the silicone tube may coincide with each other.

[0062] In the present invention, the plane where the rod core is located can be perpendicular to the radial plane of the silicone tube.

[0063] In the present invention, the size, position, number, etc. of the drug release holes of the silicone tube can be adjusted according to the actual demand for drug release.

[0064] In the present invention, in the silicone tube containing drug release holes, the ratio of the pore diameter of the drug release holes to the outer diameter of the silicone tube can be (0.0001-0.5):1, preferably (0.002-0.4):1, for example 0.06:1, 0.14:1 or 0.23:1, and more preferably (0.005-0.2):1.

[0065] In the present invention, the diameter of the drug release hole is preferably 1 μm-1000 μm, more preferably 10-600 μm, such as 10, 20, 50, 100, 150, 250, 350, 450 or 550 μm, preferably 250-450 μm.

[0066] In the present invention, in the silicone tube containing drug release holes, the total area of ​​the drug release holes can be adjusted according to the actual drug release amount requirements. For example, the ratio of the total area of ​​the drug release holes to the external surface area of ​​the silicone tube can be (0.00001-0.4):1, preferably (0.0001-0.35):1, and more preferably (0.0005-0.3):1, for example, 0.0005:1, 0.001:1, 0.005:1, 0.01:1, 0.05:1, 0.1:1 or 0.2:1.

[0067] In the present invention, the number of the drug release holes is preferably >1, more preferably 1-1000000, for example 1, 2, 5, 10, 20, 50, 100, 200, 500, 1000, 5000, 10000, 50000, 100000, 500000 or 1000000.

[0068] In the present invention, preferably, the position of the drug release hole satisfies the following conditions: the silicone tube comprises a first end face and a second end face which are arranged opposite to each other, the distance between the first end face and the second end face is the total length of the silicone tube, and a plurality of drug release holes are arranged in the silicone tube.

[0069] When the number of the drug release holes is 1, the distance from the center point of the drug release hole to the first end surface of the silicone tube containing the drug release hole may be 0-100% of the length of the silicone tube but not 0 and 100%. Preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release hole is 0.1%-99.9% of the length of the silicone tube, and more preferably 1%-99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%.

[0070] When the number of drug release holes is ≥2, the distance between the center points of the drug release holes may satisfy the following conditions:

[0071] When the planes of any two of the drug release holes are not on the same radial section of the silicone tube, in the axial section direction of the silicone tube, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes may be 0-100% of the length of the silicone tube but not 0 and 100%, preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is 0.1%-99.9% of the length of the silicone tube, more preferably 1%-99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%, and the distance between the center points of adjacent drug release holes may be 0.001-80mm.

[0072] When the number of drug release holes is ≥2, the distance between the center points of the drug release holes may also meet the following conditions:

[0073] When the planes of any two of the drug release holes are on the same radial section of the silicone tube, in the circumferential direction of the radial section of the silicone tube, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes may be 0-100% of the length of the silicone tube but not 0 and 100%. Preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is 0.1%-99.9% of the length of the silicone tube, and more preferably 1%-99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%. The circumferential distance between the center points of adjacent drug release holes may be (2-10)πmm.

[0074] In a preferred embodiment, in the silicone tube containing a drug release hole, the pore diameter of the drug release hole is 350 μm, the ratio of the pore diameter of the drug release hole to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release hole is 1, and the position of the drug release hole satisfies the following conditions: the distance from the center point of the drug release hole to the first end face of the silicone tube containing the drug release hole is 50% of the length of the silicone tube.

[0075] In a preferred embodiment, in the silicone tube containing drug release holes, the pore diameter of the drug release holes is 350 μm, the ratio of the pore diameter of the drug release holes to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release holes is 2, and the positions of the drug release holes meet the following conditions: the planes of the two drug release holes are not on the same radial section of the silicone tube, and in the axial section direction of the silicone tube, the distance from the center point of any drug release hole to the first end face of the silicone tube containing the drug release holes is 50% of the length of the silicone tube, and the distance between the center points of the two drug release holes is 0.3 cm.

[0076] In a preferred embodiment, in the silicone tube containing drug release holes, the pore diameter of the drug release holes is 350 μm, the ratio of the pore diameter of the drug release holes to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release holes is 1, and the position of the drug release holes satisfies the following conditions: the distance from the center point of the drug release hole to the first end face of the silicone tube containing the drug release holes is 7.5% of the length of the silicone tube.

[0077] In the present invention, the drug-releasing holes can be obtained by drilling with a laser or mechanical method.

[0078] In the present invention, the raw material composition of the silicone tube preferably includes the following components in parts by weight:

[0079] R-vinyl silicone rubber: 100 parts;

[0080] Reinforcing agent: 20-80 parts;

[0081] Hydrogenated silicone oil: 0.3-3.0 parts;

[0082] Catalyst: 0.000002-1 part;

[0083] Wherein, R in the R-vinyl silicone rubber is preferably a substituted or unsubstituted C1-C5 straight-chain alkane or branched alkane, a substituted or unsubstituted C6-C20 aromatic hydrocarbon, and more preferably a substituted or unsubstituted C1-C3 straight-chain alkane, such as methyl.

[0084] When the R is a methyl group, the R-vinyl silicone rubber is a methyl vinyl silicone rubber.

[0085] The vinyl content in the R-vinyl silicone rubber may be 0.10 mol%-0.50 mol%, for example, 0.18 mol% or 0.23 mol%.

[0086] Among them, the reinforcing agent can be a conventional reinforcing agent in the art that can improve the hardness of the R-vinyl silicone rubber, such as one or more of white carbon black, diatomaceous earth, quartz powder, silicon powder, calcium carbonate, aluminum hydroxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate and calcium carbonate, such as white carbon black.

[0087] The weight proportion of the reinforcing agent is preferably 30-50 parts, for example 40 parts.

[0088] The content of Si-H groups in the hydrogen-containing silicone oil may be 0.18-1.6 mol%, preferably 0.5-1 mol%, such as 0.75 mol%.

[0089] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber may be (0.5-10):1, such as 1.2:1 or 2.5:1.

[0090] The catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil, such as a platinum catalyst.

[0091] The weight proportion of the catalyst is preferably 0.000005-0.5 parts, such as 0.00001 parts, 0.0098 parts or 0.21 parts.

[0092] The raw material composition of the silicone tube containing drug-releasing holes may further include an inhibitor, and the inhibitor is used to inhibit the addition reaction between R-vinyl silicone rubber and hydrogen-containing silicone oil at room temperature.

[0093] The inhibitor may be an acetylenic alcohol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol.

[0094] The weight portion of the inhibitor may be 0.03-2.0 parts, for example 0.7 parts.

[0095] In a preferred embodiment, the silicone tube can be made by the following method:

[0096] S1. The R-vinyl silicone rubber and the reinforcing agent are mixed to obtain a mixture A;

[0097] S2. The mixture A is divided into component A1 and component A2, the component A1 and the hydrogen-containing silicone oil are mixed to obtain component B1, and the component A2 and the catalyst are mixed to obtain component B2;

[0098] S3. The component B1 and the component B2 are mixed to obtain a mixture B, and catalytic addition is performed to obtain the silicone tube.

[0099] In the present invention, the white carbon black can be pretreated by conventional methods in the art, and the pretreatment is preferably drying at 130° C. for 24 hours for standby use.

[0100] In the present invention, the R-vinyl silicone rubber and the reinforcing agent are preferably pretreated before mixing. The pretreatment may be drying. The drying operation may be conventional in the art, for example, drying the R-vinyl silicone rubber in a 40° C. oven for 12 hours, and for example, drying the reinforcing agent in a 110° C. oven for 12 hours.

[0101] In step S1, the mixing operation can be conventional in the art, for example, the R-vinyl silicone rubber and the reinforcing agent are kneaded in a vacuum kneader to obtain a rubber compound, and the rubber compound is re-milled on an open mill. The reinforcing agent is preferably added in 10 parts each time. The roller distance of the open mill can be adjusted to thin the rubber compound through pressing so that the reinforcing agent is evenly dispersed.

[0102] In step S2, when the silicone tube containing the drug-releasing holes further comprises an inhibitor, the inhibitor, component A1 and the hydrogen-containing silicone oil are mixed to obtain component B1.

[0103] In step S2, the preparation method of the component B1 can be to re-mill the component A1 in an open mill, and add the hydrogen-containing silicone oil and the inhibitor.

[0104] In step S2, the preparation method of the component B2 can be to add the component A2 dropwise into the catalyst, and continuously shorten the roller distance to perform thin pass.

[0105] In step S3, the mass ratio of the component B1 to the component B2 in the mixture B may be 1:1.

[0106] In step S3, the mixture B can be prepared by mixing and extruding component B1 and component B2 in an open mixing mill.

[0107] In step S3, the catalytic addition step may be to subject the mixture B to a first sulfurization treatment and a second sulfurization treatment in sequence.

[0108] The first vulcanization treatment is preferably carried out in a front drying tunnel. The temperature of the first vulcanization treatment may be 300° C. The time of the first vulcanization treatment may be 5 seconds. The first vulcanization treatment may preliminarily set the rubber material at high temperature.

[0109] The second vulcanization treatment is preferably carried out in a post-drying tunnel. The temperature of the second vulcanization treatment may be 240° C. The time of the second vulcanization treatment may be 2 minutes. The second vulcanization treatment can fully vulcanize the rubber material.

[0110] In the present invention, the silicone tube containing the drug-releasing holes can be obtained by punching holes in the silicone tube using a laser punching method or a mechanical punching method.

[0111] In the present invention, when the core of the perforated implant is composed of a drug-containing layer, the perforated implant is a single-layer implant.

[0112] Wherein, when the concentration of the active drug in the drug-containing layer is a single concentration, the perforated implant is a single-layer single-concentration implant.

[0113] Wherein, when the concentration of the active drug in the drug-containing layer is a gradient concentration, the perforated implant is a single-layer multi-gradient implant. The gradient is preferably 1-50 segments, such as 2 segments, 3 segments, 5 segments, 10 segments, 20 segments, or 40 segments.

[0114] In a preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release hole in the silicone tube containing the drug release hole is 350 μm, the ratio of the diameter of the drug release hole to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release hole is 1, and the position of the drug release hole meets the following conditions: the distance from the center point of the drug release hole to the first end face of the silicone tube containing the drug release hole is 50% of the length of the silicone tube, the multi-gradient is a 3-section type, which is sequentially arranged as a first gradient drug release module, a second gradient drug release module and a third gradient drug release module, and the center point of the first gradient drug release module coincides with the center point of the drug release hole.

[0115] In a preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release hole in the silicone tube containing the drug release hole is 350 μm, the ratio of the diameter of the drug release hole to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release holes is 2, and the positions of the drug release holes meet the following conditions: the two drug release holes are not on the same radial section of the silicone tube, in the axial section direction of the silicone tube, the distance from the center point of any drug release hole to the first end face of the silicone tube containing the drug release hole is 50% of the length of the silicone tube, and the distance between the center points of the two drug release holes is 0.3 cm; the multi-gradient can be a 3-segment type, which is sequentially arranged as a first gradient drug release module, a second gradient drug release module and a third gradient drug release module, and the center points of the first gradient drug release module and the second gradient drug release module coincide with the center points of the two drug release holes respectively.

[0116] In a preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release hole in the silicone tube containing the drug release hole is 350 μm, the ratio of the diameter of the drug release hole to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release holes is 3, and the positions of the drug release holes meet the following conditions: the 3 drug release holes are not on the same radial section of the silicone tube, in the axial section direction of the silicone tube, the distance from the center point of any drug release hole to the first end face of the silicone tube containing the drug release hole is 50% of the length of the silicone tube, and the distance between the center points of adjacent drug release holes is 0.3 cm; the multi-gradient can be a 3-segment type, which is sequentially arranged as a first gradient drug release module, a second gradient drug release module and a third gradient drug release module, and the center points of the first gradient drug release module, the second gradient drug release module and the third gradient drug release module coincide with the center points of the 3 drug release holes respectively.

[0117] In the present invention, when the rod core of the perforated implant further includes a boosting layer composited on the drug-containing layer, the perforated implant is a double-layer implant.

[0118] Preferably, the planes where the drug-containing layer and the booster layer are located are perpendicular to the radial plane of the silicone tube.

[0119] Preferably, when the number of the drug-releasing hole is 1, the center point of the drug-containing layer coincides with the center point of the drug-releasing hole.

[0120] Preferably, when the number of the drug-releasing holes is greater than 1, the positional relationship between the center point of the drug-containing layer and the center point of the drug-releasing hole can be selected according to the required release amount of the active drug.

[0121] The present invention also provides a method for preparing the perforated implant as described above, which comprises the following steps: filling the drug composition or the stick core into the silicone tube containing the drug release hole.

[0122] The present invention also provides an application of the stick core or the perforated implant as a release rate regulating medium in a sustained-release preparation.

[0123] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0124] The reagents and raw materials used in the present invention are commercially available.

[0125] The positive and progressive effect of the present invention is that the present invention adopts a solid column pressing method to compress and mold the active drug and the auxiliary materials to obtain the stick core, which not only solves the problem of drug waste or unstable drug release in the powder-type drug core, but also solves the problem of drug instability in the preparation process of the silicone skeleton-type stick core. After the silicone tube is punched, the applicable scope of the drug is expanded, including conventional drugs in the field, for example, macromolecular drugs with good solubility, small molecule drugs with good solubility, macromolecular drugs with poor solubility, and small molecule drugs with poor solubility, thereby increasing the release amount of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0126] Figure 1 The in vitro release curves of Examples 1-1, 1-2, 1-3, 1-4 and 1-5.

[0127] Figure 2 The in vitro release curves of Examples 2-1, 2-2, 2-3, 2-4 and 2-5.

[0128] Figure 3 The in vitro release curves of Examples 3-1, 3-2, 3-3, 3-4 and 3-5.

[0129] Figure 4 The in vitro release curves of Examples 4-1, 4-2, 4-3, 4-4 and 4-5.

[0130] Figure 5 The in vitro release curves of Comparative Example 1, Examples 5-1, 5-2 and 5-3.

[0131] Figure 6 The in vitro release curves of Comparative Example 2, Examples 6-1, 6-2 and 6-3.

[0132] Figure 7 The in vitro release curves of Examples 7-1 and 7-2.

[0133] Figure 8 The in vitro release curves of Examples 8-1 and 8-2.

[0134] Fig. 9 The in vitro release curves of Examples 9-1 and 9-2.

[0135] Fig.10 The in vitro release curves of Examples 10-1 and 10-2.

[0136] Fig.11 The in vitro release curves of Examples 11-1, 11-2 and 11-3.

[0137] Fig.12 The in vitro release curves of Examples 11-4, 11-5 and 11-6.

[0138] Fig.13 The in vitro release curves of Examples 12-1, 12-2 and 12-3.

[0139] Fig.14 The in vitro release curves of Examples 13-1, 13-2 and 13-3.

[0140] Fig.15 The in vitro release curves of Examples 14-1, 14-2 and 14-3.

[0141] Fig.16 The in vitro release curves of Examples 15-1, 15-2, 15-3 and 15-4.

[0142] Fig.17 The in vitro release curves of Examples 16-1, 16-2, 16-3 and 16-4.

[0143] Fig.18 The in vitro release curves of Examples 17-1, 17-2 and 17-3.

[0144] Fig.19 The in vitro release curves of Examples 18-1, 18-2 and 18-3.

[0145] Fig. 20 The in vitro release curves of Examples 19-1, 19-2 and 19-3.

[0146] Fig.21 This is a flow chart for the preparation of silicone tubes.

[0147] Fig. 22 Schematic diagram of the perforated implant of Examples 11-14.

[0148] Fig.23 Schematic diagram of the perforated implant of Examples 1-4.

[0149] Fig.24 Schematic diagram of the perforated implant of Example 15.

[0150] Fig.25 Schematic diagram of the perforated implant of Examples 5-1 and 6-1.

[0151] Fig.26 Schematic diagram of the perforated implant of Examples 5-2 and 6-2.

[0152] Fig. 27 Schematic diagram of the perforated implant of Examples 5-3 and 6-3.

[0153] Fig.28 Schematic diagram of the perforated implants of Examples 7-2, 8-2, 9-2 and 10-2.

[0154] The following are the descriptions of the reference numerals:

[0155] 1-drug release hole; 2-silicone tube; 3-length of silicone tube; 4-outer diameter of silicone tube; 5-hole diameter of drug release hole; 6-distance from the center point of drug release hole to the end point of silicone tube; 7-distance between the center points of adjacent drug release holes; 8-sealing glue; 9-drug-containing layer; 901-first drug release module; 902-second drug release module; 903-third drug release module; 10-direction of drug release; 11-boosting layer. DETAILED DESCRIPTION

[0156] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0157] The instruments, raw materials and their sources used in the following examples are shown in Table 1:

[0158] Table 1

[0159]

[0160]

[0161] The preparation process of the silicone tube in the following embodiment is as follows Fig.21 shown.

[0162] The formula of the silicone tube containing the drug release hole of the perforated implant of Example 1-19 and Comparative Example 1-2 is as follows:

[0163] Name of raw and auxiliary materials Dosage or content Methyl vinyl silicone rubber 100 copies Vinyl content in methyl vinyl silicone rubber 0.18％ Content of Si-H group in hydrogen silicone oil 0.75％ Molar ratio of Si-H groups in hydrogenated silicone oil to vinyl groups in methyl vinyl silicone rubber 1.2:1 White carbon black (water contact angle>90°) 40 servings Platinum catalyst 0.00001 copies Methylbutynol 0.7 parts Extrusion speed <![CDATA[7.0r·min -1 ]]> First vulcanization temperature and time 300℃、5s Second vulcanization temperature and time 240℃, 2min

[0164] Among them, the water contact angle of silica is the static water contact angle of the material. Its measurement utilizes the principle of optical appearance projection to test. During use, the volume of the water drop is set using the test software, and then the syringe needle drops the water droplet of the set volume on the surface of the sample to be tested. Under the background of LED light source, the image of the droplet is projected onto the automatic image analysis system using a screen micrometer for measurement.

[0165] The preparation method of the silicone tube containing drug release holes of the perforated implant of Example 1-19 and Comparative Example 1-2 is as follows:

[0166] S1. Dry the methyl vinyl silicone rubber in an oven at 40°C for 12 hours, and dry the white carbon black in an oven at 110°C for 12 hours. Mix the methyl vinyl silicone rubber and white carbon black in a vacuum kneader to obtain a rubber compound, and re-mix the rubber compound on an open mill to obtain a mixture A;

[0167] S2. The mixture A is divided into component A1 and component A2, component A1 is re-refined in an open mill, and hydrogen-containing silicone oil and methyl butynol are added to obtain component B1; component A2 is dropwise added with a platinum catalyst, the roller distance is continuously shortened, and thin-pass is performed to obtain component B2; the mass ratio of component B1 to component B2 is 1:1;

[0168] S3. The components B1 and B2 are mixed and extruded in an open mill to obtain a mixture B, and the mixture B is sequentially subjected to a first vulcanization treatment and a second vulcanization treatment to obtain a silicone tube;

[0169] S4. The silicone tube is punched with laser to obtain a silicone tube with drug release holes. The silicone tube has a length of 4 cm and an outer diameter of 2.4 mm.

[0170] The preparation methods of the rod cores of Examples 1-19 and Comparative Examples 1-2 are as follows:

[0171] The drug composition is formed by solid column pressing, and the drug-containing layer is obtained by pressing at 0.3 MPa;

[0172] When a boosting layer is included, the raw material of the boosting layer is formed by solid column pressing, and pressed at 0.3 MPa, and the boosting layer is compounded on the drug-containing layer;

[0173] The prepared rod core has a length of 7 mm and a diameter of 2 mm, and the plane where the rod core is located and the radial plane of the silicone tube are perpendicular to each other.

[0174] (I) Process investigation of drug release holes in perforated implants

[0175] I. Investigation of the diameter of the drug release channel of perforated implants

[0176] The schematic diagram of the perforated implant of Examples 1-4 is as follows Fig.23 shown.

[0177] Example 1 Insulin perforated implant

[0178] The formula composition of the stick core:

[0179]

[0180] Example 2 Semaglutide perforated implant

[0181] The formula composition of the stick core:

[0182]

[0183]

[0184] Example 3 Metformin perforated implant

[0185] The formula composition of the stick core:

[0186]

[0187] Example 4 Paliperidone perforated implant

[0188] The formula composition of the stick core:

[0189]

[0190] II. Investigation of the number of drug release holes in perforated implants

[0191] The schematic diagram of the perforated implant of Example 5-6 is as follows Figure 25-27 shown.

[0192] Example 5, Comparative Example 1 Insulin perforated implant

[0193] The formula composition of the stick core:

[0194]

[0195]

[0196] Example 6, Comparative Example 2 The formula composition of the semaglutide perforated implant stick core is:

[0197]

[0198]

[0199] III. Investigation of the location of the drug release holes in perforated implants

[0200] The schematic diagrams of the perforated implants of Examples 7-10 are as follows: Fig.24 and 28 shown.

[0201] Example 7 Insulin perforated implant

[0202] The formula composition of the stick core:

[0203]

[0204] Example 8 Semaglutide perforated implant

[0205] The formula composition of the stick core:

[0206]

[0207] Example 9 Metformin Perforated Implant

[0208] The formula composition of the stick core:

[0209]

[0210] Example 10 Paliperidone perforated implant

[0211] The formula composition of the stick core:

[0212]

[0213] (II) Investigation of the core formulation of perforated implants

[0214] I. Single-layer single-gradient perforated implant

[0215] The pore parameters of the silicone tube containing the drug release holes of the perforated implants of Examples 11, 13, 15-19 are as follows:

[0216]

[0217] The pore parameters of the silicone tube containing the drug release holes of the perforated implants of Examples 12 and 14 are as follows:

[0218]

[0219] (i) Investigation of the types of excipients in the drug-containing layer of the single-layer single-gradient perforated implant core

[0220] The schematic diagram of the perforated implant of Examples 11-14 is as follows Fig. 22 shown.

[0221] Example 11 Exenatide perforated implant

[0222] The formula composition of the stick core:

[0223]

[0224] Example 12 Metformin perforated implant

[0225] The formula composition of the stick core:

[0226]

[0227]

[0228] (ii) Investigation of drug-excipient ratio of drug-containing layer in single-layer single-gradient perforated implant core

[0229] Example 13 Exenatide perforated implant

[0230] The formula composition of the stick core:

[0231]

[0232] (iii) Investigation of the ratio of poorly soluble skeleton material to hydrophilic gel material in the drug-containing layer of the sustained-release excipients of the single-layer single-gradient perforated implant rod core

[0233] Example 14 Metformin perforated implant

[0234] The formula composition of the stick core:

[0235]

[0236] II. Single-layer multi-gradient perforated implant

[0237] (i) Investigation of active drug concentration in each gradient drug release module of the single-layer multi-gradient perforated implant core

[0238] The schematic diagram of the perforated implant of Example 15 is as follows Fig.24 shown.

[0239] Example 15 Semaglutide perforated implant

[0240]

[0241] III. Double-layer perforated implant

[0242] (i) Investigation of the types of excipients in the drug-containing layer of the double-layer perforated implant core

[0243] Example 16 Levothyroxine Sodium Perforated Implant

[0244] The formula composition of the stick core:

[0245]

[0246] (ii) Investigation of the mass ratio of the sustained-release excipients and fillers in the drug-containing layer of the double-layer perforated implant core

[0247] Example 17 Levothyroxine Sodium Perforated Implant

[0248] The formula composition of the stick core:

[0249]

[0250] (iii) Investigation of the types of expansion materials in the core booster layer of the double-layer perforated implant Example 18 Levothyroxine sodium perforated implant

[0251] The formula composition of the stick core:

[0252]

[0253] (iv) Investigation of the amount of expansion material used in the core boosting layer of a double-layer perforated implant Example 19 Levothyroxine Sodium Perforated Implant

[0254] Prescription composition of medicine sticks:

[0255]

[0256] Effect Example: Establishment of Release Determination Method

[0257] 1. Testing conditions

[0258] (1) Chromatographic conditions of exenatide

[0259] Chromatographic column: C18 column (250 mm × 4.60 mm, 5 μm);

[0260] Mobile phase: Phase A: 0.08% trifluoroacetic acid acetonitrile solution;

[0261] Mobile phase: Phase B: 0.08% trifluoroacetic acid in water;

[0262] The proportion of mobile phase A varied with time from 28% to 55% (0 to 25 min);

[0263] Flow rate: 1.0 mL min-1;

[0264] Detection wavelength: 214nm;

[0265] Column temperature: 30°C;

[0266] Injection volume: 20 μL;

[0267] (2) Chromatographic conditions of estradiol

[0268] Chromatographic column: C18 column (250mm×4mm, 5μm)

[0269] Mobile phase: acetonitrile-water (55:45, v / v)

[0270] Column temperature: 25°C

[0271] Detection wavelength: 202nm

[0272] Flow rate: 0.8 mL min-1

[0273] (3) Chromatographic conditions of semaglutide

[0274] Chromatographic column: C18 column (250 mm × 4.60 mm, 5 μm);

[0275] Mobile phase: 0.2 mol·L-1 sulfate buffer-acetonitrile (60:40, v / v);

[0276] Column temperature: 30°C;

[0277] Detection wavelength: 192nm;

[0278] Flow rate: 1 mL min-1;

[0279] Injection volume: 20 μL

[0280] (4) Chromatographic conditions of levothyroxine sodium

[0281] Chromatographic column: SinoDetectHCL-C18 column (4.6×250mm, 5μm)

[0282] Mobile phase: acetonitrile-0.1% TFA (50:50, v / v)

[0283] Column temperature: 30°C

[0284] Detection wavelength: 225nm

[0285] Flow rate: 1mL min-1

[0286] Injection volume: 20 μL

[0287] (5) Chromatographic conditions for metformin

[0288] Chromatographic column: C18 column (4.6 mm × 150 mm, 5 μm);

[0289] Mobile phase: methanol: water (10:90, v / v) (phosphoric acid and triethylamine adjusted to pH 3.5); Column temperature: room temperature;

[0290] Detection wavelength: 233nm;

[0291] Flow rate: 1.0 mL min-1;

[0292] Injection volume: 20 μL.

[0293] (6) Chromatographic conditions of insulin

[0294] Chromatographic column: C18 column (250 mm × 4.60 mm, 5 μm);

[0295] Mobile phase: methanol: water (65:35, v / v, 0.1% TFA added to total volume)

[0296] Column temperature: 40°C

[0297] Detection wavelength: 214nm

[0298] Flow rate: 1.0 mL min-1

[0299] Injection volume: 20 μL

[0300] (7) Chromatographic conditions of paliperidone

[0301] Chromatographic column: C8 column (4.6 × 100 mm, 2.7 μm);

[0302] Mobile phase: methanol:acetonitrile:water (5:25:70, v / v) (pH adjusted to 3 with phosphoric acid and triethylamine);

[0303] Column temperature: 35°C;

[0304] Detection wavelength: 270nm;

[0305] Flow rate: 0.8 mL min-1;

[0306] Injection volume: 20 μL.

[0307] 2. Release results

[0308] (I) Investigation of drug release channel technology of perforated implants

[0309] I. Investigation of the diameter of the drug release channel of perforated implants

[0310] (1) The release results of the insulin monolayer single gradient perforated implant model (daily release dose μg) are shown in the following table and Figure 1 shown.

[0311] Time (d) Example 1-1 Example 1-2 Examples 1-3 Examples 1-4 Examples 1-5 1 16.39 88.06 127.41 206.48 304.13 5 37.30 102.61 181.88 308.61 542.01 10 80.32 64.71 95.19 204.94 244.78 15 19.74 46.95 88.11 113.42 254.86 20 27.15 41.17 89.64 234.13 197.21 25 19.09 34.78 52.12 97.58 105.48 30 15.99 27.47 61.85 152.74 173.38 35 29.58 54.69 80.33 105.25 142.01 40 13.19 53.43 92.78 188.53 244.76 45 19.24 28.22 65.37 101.09 109.86 50 22.38 25.59 64.79 110.26 132.49 55 16.52 30.93 78.22 95.09 105.66 60 12.24 17.72 65.71 112.84 132.41

[0312] (2) The release results of the semaglutide monolayer single gradient perforated implant model (daily release dose μg) are shown in the following table and Figure 2 shown.

[0313]

[0314]

[0315] (3) The release results of metformin monolayer single gradient perforated implant model (daily release dose μg) are shown in the following table and Figure 3 shown.

[0316] Time (d) Example 3-1 Example 3-2 Example 3-3 Embodiment 3-4 Embodiment 3-5 1 242.55 249.74 221.16 394.99 573.94 5 404.68 364.32 479.23 876.11 1218.81 10 360.44 185.24 330.33 732.05 1312.67 15 289.73 226.15 449.85 438.72 823.73 20 173.87 257.83 329.21 462.53 395.88 25 117.74 243.31 212.97 241.19 377.12 30 108.58 182.03 163.31 131.78 485.39 35 108.89 154.12 181.07 110.05 316.77 40 99.35 214.81 191.48 132.91 385.43 45 144.47 135.04 178.40 199.97 289.07 50 127.74 124.09 211.37 229.07 201.41 55 86.13 99.04 128.83 114.53 322.11 60 107.29 149.33 92.46 141.72 98.71

[0317] (4) The release results of the paliperidone monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table and Figure 4 shown.

[0318]

[0319]

[0320] It can be seen from Examples 1-4 that the implant is applicable to soluble macromolecular drugs, poorly soluble macromolecular drugs, poorly soluble macromolecular drugs and soluble small molecule drugs.

[0321] Further analysis of Examples 1-4 shows that in the early stage of drug release, when the pore diameter is greater than 450 μm, a sudden drug release phenomenon will occur, the drug is released quickly, and then the release amount will drop sharply, resulting in insufficient power in the later stage, making it difficult to achieve long-term drug release. When the pore diameter is less than 250 μm (except for metformin), the release amount is relatively stable throughout the release cycle, but the daily release amount of the preparation is lower than that of a larger pore diameter (such as greater than 250 μm).

[0322] II. Investigation of the number of drug release holes in perforated implants

[0323] (1) The release results of the insulin monolayer single gradient perforated implant model (daily release dose μg) are shown in the following table and Figure 5 shown.

[0324] Time (d) Comparative Example 1 Example 5-1 Example 5-2 Example 5-3 1 0 127.41 138.31 199.43 5 0 181.88 292.65 373.12 10 0 95.11 133.37 165.90 15 0 88.16 88.52 110.27 20 0 89.64 93.06 92.03 25 0 52.12 79.67 66.81 30 0 61.85 83.37 122.28 35 0 80.33 53.45 72.76 40 0 92.78 86.96 121.85 45 0 65.37 68.52 98.21 50 0 64.79 96.12 57.87 55 0 78.22 98.02 53.43 60 0 65.71 74.28 84.67

[0325] (2) The release results of the semaglutide monolayer single gradient perforated implant model (daily release dose μg) are shown in the following table and Figure 6 shown.

[0326]

[0327]

[0328] In the initial stage of drug release, the daily release amount of the preparation will increase with the increase in the number of drug release holes, among which implants with double and triple drug release holes will have a burst release phenomenon.

[0329] III. Investigation of the location of the drug release holes in perforated implants

[0330] (1) The release results of the insulin monolayer single gradient perforated implant model (daily release dose μg) are shown in the following table and Figure 7 shown.

[0331] Time (d) Example 7-1 Example 7-2 Time (d) Example 7-1 Example 7-2 1 127.41 134.19 35 80.33 61.78 5 181.88 151.16 40 92.78 69.45 10 95.11 120.63 45 65.37 103.48 15 88.33 125.43 50 64.79 112.69 20 89.64 109.94 55 78.22 91.39 25 52.12 96.01 60 65.71 91.67 30 61.85 114.27

[0332] (2) The release results of the semaglutide monolayer single gradient perforated implant model (daily release dose μg) are shown in the following table and Figure 8 shown.

[0333] Time (d) Example 8-1 Example 8-2 Time (d) Example 8-1 Example 8-2 1 155.75 161.11 35 221.57 167.18 5 400.93 428.42 40 169.64 163.57 10 260.52 328.66 45 236.51 182.89 15 204.12 214.34 50 227.13 151.44 20 209.81 193.46 55 263.09 104.47 25 127.82 218.69 60 188.56 144.83 30 220.71 155.92

[0334] (3) The release results of metformin monolayer single gradient perforated implant model (daily release dose μg) are shown in the following table and Fig. 9 shown.

[0335] Time (d) Example 9-1 Example 9-2 Time (d) Example 9-1 Example 9-2 1 249.72 310.95 35 154.12 155.20 5 364.32 451.08 40 214.81 156.59 10 185.21 294.16 45 135.04 150.63 15 226.15 273.99 50 124.09 118.99 20 257.70 192.67 55 99.04 205.77 25 243.31 182.01 60 149.33 157.41 30 182.03 233.67

[0336] (4) The release results of the paliperidone monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table and Fig.10 shown.

[0337] Time (d) Example 10-1 Example 10-2 Time (d) Example 10-1 Example 10-2 1 213.12 233.10 35 180.61 198.26 5 364.51 400.52 40 170.19 217.62 10 389.41 319.83 45 192.94 201.98 15 334.67 261.55 50 233.78 231.28 20 211.21 176.18 55 152.96 170.84 25 213.15 201.23 60 140.30 127.11 30 208.48 208.70

[0338] The results of drug release curves show that the change in the position of the single-channel drug release hole does not have a significant effect on drug release, and the release curves are relatively close with no significant difference.

[0339] (II) Investigation of the core formulation of perforated implants

[0340] I. Single-layer single-gradient perforated implant

[0341] (i) The results of the investigation of the types of excipients in the drug-containing layer of the single-layer single-gradient perforated implant core (daily release dose μg) are as follows: Figure 11-13 shown.

[0342] Time (d) Example 11-1 Example 11-2 Example 11-3 Example 11-4 Example 11-5 Example 11-6 1 2.16 2.46 39.66 200.09 150.98 0.00 5 18.98 12.29 76.54 275.29 130.20 0.00 10 42.98 11.37 73.77 200.22 121.19 0.00 15 36.28 21.17 62.62 29.72 32.68 379.45 20 42.77 28.63 74.66 33.78 22.74 100.13 25 39.82 12.83 62.07 42.54 37.42 87.27 30 48.12 19.78 62.44 37.12 73.01 92.87 35 46.77 22.96 54.36 29.34 52.99 91.68 40 39.99 7.12 60.99 55.87 47.11 10.09 45 16.13 0.00 40.57 28.67 47.99 3.48 50 4.21 0.00 37.04 23.88 69.02 18.02 55 0.00 0.00 31.51 41.83 50.01 3.23 60 0.00 0.00 34.43 37.43 20.88 2.12

[0343] As can be seen from Example 11, when the sustained-release excipient is a poorly soluble skeleton material (Eutrific S100, calcium alginate, ethyl cellulose), the release curve is relatively stable. The difference is that the release control ability is too strong, which may be due to the poor water solubility of Eudragit S100 and calcium alginate, and the release stagnation phenomenon is shown in the early stage of drug release. Relatively speaking, ethyl cellulose shows a better drug release trend.

[0344] In the release curve of hydrophilic gel material as sustained-release excipient, PEO N80 has a stronger sustained-release effect on drugs due to its high viscosity and high degree of hydration. Therefore, the drug release amount is extremely low in the early stage. Later, due to the continuous dissolution of the hydration layer on the surface of the medicine stick, the local drug is exposed to the surface of the preparation and the release amount increases, but most of it is still wrapped inside by the hydration layer formed by PEO, and the release amount gradually decreases. PLGA and HPMC K15M have no obvious drug release stagnation phenomenon. During the in vitro release process, it can be clearly seen that the preparation produces swelling, which can also be called "tube swelling phenomenon". Considering that the silicone tube needs to have certain mechanical properties after implantation in the human body to ensure its long-term drug release stability, when the hydrophilic gel skeleton material is used alone as a sustained-release material, the effect is poorer than that of the poorly soluble skeleton material.

[0345]

[0346] From the release curve in the figure below, we can conclude that when the hydrophilic gel skeleton material is HPMC K15M, it can interact with ethyl fiber to achieve an ideal sustained-release effect.

[0347] (2) The release results of the drug-excipient ratio study of the drug-containing layer of the single-layer single-gradient perforated implant core (daily release dose μg) are shown in the following table and Fig.14 shown.

[0348]

[0349] From the above, it can be seen that when the drug-excipient ratio is 1:5, the drug release is stable, and there is no obvious drug release burst or stagnation phenomenon.

[0350] (3) The release results (daily release dose μg) of the ratio of the insoluble skeleton material to the hydrophilic gel material in the drug-containing layer of the single-layer single-gradient perforated implant stick core are shown in the following table and Fig.15 shown.

[0351]

[0352]

[0353] When EC:HPMC K15M=2:1, the drug release curve was relatively stable. When the HPMC K15M content increased, the initial burst release of the drug increased instead.

[0354] II. Single-layer multi-gradient perforated implant

[0355] (1) The release results of the drug ratio in each stage of the single-layer multi-gradient perforated implant (daily release dose μg) are as follows: Fig.16 shown.

[0356] Time (d) Example 15-1 Example 15-2 Example 15-3 Example 15-4 1 40.35 39.02 89.18 121.63 5 47.26 92.03 150.07 197.36 10 90.42 109.79 170.19 220.91 15 62.15 86.81 185.90 202.24 20 67.04 88.96 151.22 189.35 25 67.11 94.95 152.62 187.37 30 68.97 75.15 151.51 123.06 35 67.99 81.95 135.76 116.25 40 68.09 67.42 91.94 94.89 45 58.28 58.04 97.85 85.82 50 58.44 64.65 68.19 49.09 55 52.80 63.59 71.34 45.54 60 56.71 47.57 63.98 41.49

[0357] III. Double-layer implant

[0358] (1) The release results of the drug-containing excipient types of the double-layer perforated implant core (daily release dose μg) are shown in the following table and Fig.17 shown.

[0359]

[0360]

[0361] Both PEO WSR-303 and PEO WSRN-750 have a good and stable release, but the higher viscosity of PEO WSR303 in the drug-containing layer may affect the appearance of the entire implant.

[0362] (2) The release results (daily release dose μg) of the double-layer perforated implant core drug-containing layer sustained-release excipients and fillers are shown in the following table and Fig.18 shown.

[0363]

[0364] The results showed that when the amount of PEO WSRN-750 was 20 mg, the drug could not be fully suspended and the drug release was insufficient in the later stage. However, as the amount of PEO WSRN-750 increased, the drug release slowed down. When the amount of PEO WSRN-750 was 60 mg, the drug release rate decreased.

[0365] (3) The release results (daily release dose μg) of the expansion material in the core booster layer of the double-layer perforated implant are shown in the following table and Fig.19 shown.

[0366]

[0367] The results showed that the change of PEO molecular weight within the selected range had no significant effect on drug release. In addition, as the molecular weight of PEO increased, the viscosity increased and the moldability of the excipient powder improved.

[0368] (4) The release results (daily release dose μg) of the expansion material used in the double-layer perforated implant core booster layer are shown in the following table and Fig. 20 shown.

[0369]

[0370] The dosage of PEO WSR N60K within the selected range had no significant effect on drug release.

Claims

1. A rod core for a perforated implant, characterized in that: The method comprises a drug-containing layer, wherein the drug-containing layer comprises an active drug and excipients; Wherein, the excipients include sustained-release excipients; the molecular weight of the sustained-release excipients is 10-10 million; The drug-excipient ratio is 1:(0.01-100); the drug-excipient ratio represents the mass ratio of the active drug to the excipient in the drug-containing layer; Optionally, the rod core of the perforated implant further includes a boosting layer composited on the drug-containing layer.

2. The rod core for perforated implant according to claim 1, characterized in that: The active drug includes an active drug with a drug solubility of >10 mg / mL and a drug molecular weight of greater than 800 Da, preferably an active drug with a drug solubility of >30 mg / mL and a drug molecular weight of greater than 800 Da, such as one or more of exenatide, semaglutide, Centella asiatica glycosides and human growth hormone; And / or, the active drug includes an active drug with a drug solubility of >10 mg / mL and a drug molecular weight of less than or equal to 800 Da, preferably an active drug with a drug solubility of >30 mg / mL and a drug molecular weight of less than or equal to 800 Da, such as metformin and / or doxorubicin hydrochloride; And / or, the active drug comprises an active drug with a drug solubility of ≤10 mg / mL and a drug molecular weight greater than 800 Da, preferably an active drug with a drug solubility of ≤5 mg / mL and a drug molecular weight greater than 800 Da, such as one or more of bovine insulin, paclitaxel and levothyroxine sodium; And / or, the active drug comprises an active drug with a drug solubility of ≤10 mg / mL and a drug molecular weight of 800 Da or less, preferably an active drug with a drug solubility of ≤5 mg / mL and a drug molecular weight of 800 Da or less, such as one or more of estradiol, gestodene, levonorgestrel, meloxicam, ganciclovir, puerarin and paliperidone; and / or, the weight average molecular weight of the sustained-release excipient is 11 million to 8 million, for example, 11.71, 10,000, 44,000, 200,000, 300,000, 400,000 or 7 million; The sustained-release excipient preferably includes a poorly soluble skeleton material and / or a hydrophilic gel material; the poorly soluble skeleton material preferably has a weight average molecular weight of 20-800 million, preferably 30-700 million; more preferably includes one or more of calcium alginate, methyl cellulose, polyethylene, polyvinyl chloride, methacrylic acid-methyl acrylate copolymer and ethyl cellulose, such as ethyl cellulose; the methacrylic acid-methyl acrylate copolymer is preferably one or more of Eudragit S100, Eudragit L100, RL, RS, NE and FS, such as Eudragit S100; the hydrophilic gel material preferably has a weight average molecular weight of 10-800 million, more preferably includes one or more of hydroxypropyl methylcellulose, polyethylene oxide, sodium alginate, chitosan, agar, xanthan gum, carbomer, polyvinyl alcohol, N-vinyl amide polymer, polylactic acid-glycolic acid copolymer (PLGA) and polyethylene oxide; the hydroxypropyl methylcellulose is preferably HPMC The N-vinyl amide polymer is preferably PVP K30 and / or PVP K90; the polyethylene oxide is preferably PEO N80, PEO N-750, PEO WSR 303, PEO WSR N-12K, PEO WSR N-60K and PEO WSR 1105. And / or, the excipients further include one or more of a drug stabilizer, a filler and a suspending agent; and / or, the drug-excipient ratio is 1:(0.01-99), for example, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60 or 1:80; And / or, the mass ratio of the sustained-release excipient to the excipient is 1:(0.01-100), for example 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60, 1:80 or 1:

100.

3. The rod core for perforated implant according to claim 1, characterized in that: The concentration of the active drug in the drug-containing layer is set as a gradient concentration; the gradient is preferably 1-50 segments, such as 2 segments, 3 segments, 5 segments, 10 segments, 20 segments, or 40 segments; the gradient concentration is generally expressed as the concentration of each gradient is independent of each other; And / or, the raw materials of the boost layer include expansion materials and permeation promoters; And / or, when the stick core further includes a boosting layer, the mass ratio of the drug-containing layer to the boosting layer is (0.01-100):1, for example, 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1 or 100:1; And / or, when the stick core further includes a boosting layer, the number of the boosting layers is an integer, preferably an even number, such as 2; when the number of the boosting layers is an even number, the boosting layers are preferably respectively arranged at both ends of the drug-containing layer; And / or, the single pressing length of the rod core is 1-50 mm, such as 1 mm or 2 mm or 3 mm or 4 mm or 5 mm or 7 mm or 10 mm or 20 mm or 30 mm or 40 mm or 50 mm; the total length of the rod core can be selected according to the length of the silicone tube; And / or, the diameter of the rod core is 1-10 mm, more preferably 1-5 mm, such as 2 mm, 3 mm or 4 mm.

4. The rod core for perforated implant according to claim 3, characterized in that: When the gradient is 3 sections, the gradient is sequentially arranged as a first gradient drug release module, a second gradient drug release module and a third gradient drug release module, the concentration of the active drug in the first gradient drug release module is 0.1%-50%, such as 2%, 5% or 10%; the concentration of the active drug in the second gradient drug release module is 1%-80%, such as 10% or 20%; the concentration of the active drug in the third gradient drug release module is 1%-100%, such as 20% or 30%; the concentration of the active drug indicates the percentage of the mass of the active drug to the mass of the gradient drug release module; And / or, the expansion material in the boosting layer is polyethylene oxide, preferably polyethylene oxide with a weight average molecular weight of 100,000-700,000, such as one or more of PEO N-80, PEO N-750, PEO WSR 1105, PEO WSR 303, PEO N-12K and PEO N-60K; and / or, the permeation enhancer in the boost layer is one or more of mannitol, lactose, fructose, glucose and NaCl, such as NaCl; Among them, the mass ratio of the expansion material and the permeation promoter in the boost layer is preferably (0.01-100):1, for example, 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1 or 100:

1.

5. A method for preparing a punched implant rod core according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: compressing the active drug and the auxiliary material to obtain the drug-containing layer; Optionally, the boosting layer is composited on the drug-containing layer; Preferably, the pressing pressure is 0.01-10 MPa, such as 0.1, 0.2, 0.3, 0.5, 1, 2, 5 or 10 MPa.

6. A perforated implant, characterized in that: The invention comprises a rod core for a perforated implant as claimed in any one of claims 1 to 4 and a silicone tube with drug-releasing holes coated on the outside of the rod core.

7. The perforated implant according to claim 6, characterized in that In the silicone tube having drug release holes, the ratio of the diameter of the drug release holes to the outer diameter of the silicone tube is (0.0001-0.5):1, preferably (0.002-0.4):1, such as 0.06:1, 0.14:1 or 0.23:1, more preferably (0.005-0.2):1; And / or, in the silicone tube containing drug release holes, the ratio of the total area of ​​the drug release holes to the outer surface area of ​​the silicone tube is (0.00001-0.4):1, preferably (0.0001-0.35):1, more preferably (0.0005-0.3):1, for example 0.0005:1, 0.001:1, 0.005:1, 0.01:1, 0.05:1, 0.1:1 or 0.2:1; And / or, the diameter of the drug release hole is 1 μm-1000 μm, preferably 10-600 μm, such as 10, 20, 50, 100, 150, 250, 350, 450 or 550 μm, more preferably 250-450 μm; and / or, the number of the drug release holes is >1, preferably 1-1000000, for example 1, 2, 5, 10, 20, 50, 100, 200, 500, 1000, 5000, 10000, 50000, 100000, 500000 or 1000000; And / or, the silicone tube containing the drug-releasing holes is obtained by punching the silicone tube using a laser punching method or a mechanical punching method.

8. The perforated implant according to claim 7, characterized in that The position of the drug release hole meets the following conditions: the silicone tube comprises a first end face and a second end face which are arranged opposite to each other, the distance between the first end face and the second end face is the total length of the silicone tube, and a plurality of drug release holes are arranged in the silicone tube; Wherein, when the number of the drug release holes is 1, the distance from the center point of the drug release hole to the first end surface of the silicone tube containing the drug release hole is preferably 0-100% of the length of the silicone tube but not 0 and 100%, more preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release hole is 0.1%-99.9% of the length of the silicone tube, more preferably 1%-99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%; Wherein, when the number of drug release holes is ≥2, the distance between the center points of the drug release holes preferably satisfies the following conditions: When the planes of any two of the drug release holes are not on the same radial section of the silicone tube, in the axial section direction of the silicone tube, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is preferably 0-100% of the length of the silicone tube but not 0 and 100%, preferably 0.1%-99.9% of the length of the silicone tube, more preferably 1%-99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%; the distance between the center points of adjacent drug release holes is preferably 0.001-80mm; Wherein, when the number of drug release holes is ≥2, the distance between the center points of the drug release holes may also satisfy the following conditions: When the planes of any two of the drug release holes are on the same radial section of the silicone tube, in the circumferential direction of the radial section of the silicone tube, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is preferably 0-100% of the length of the silicone tube but not 0 and 100%, and preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is 0.1%-99.9% of the length of the silicone tube, and more preferably 1%-99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%; the distance between the center points of adjacent drug release holes on the circumference is preferably (2-10)πmm.

9. A method for preparing a perforated implant according to any one of claims 6 to 8, characterized in that: The method comprises the following steps: filling the rod core of the perforated implant according to any one of claims 1 to 4 into a silicone tube having a drug release hole.

10. Use of a rod core of a perforated implant according to any one of claims 1 to 4 or a perforated implant according to any one of claims 6 to 8 as a release rate regulating medium in a sustained-release preparation.

Images