Hollow skeleton type medicine carrying rod core and preparation method and application thereof

Abstract

The invention discloses a hollow skeleton type drug-loading rod core as well as a preparation method and application thereof. The raw material composition comprises the following components in parts by weight: 1-1000 parts of active pharmaceutical ingredients; 100 parts of R-vinyl silicone rubber; 0.45 to 20 parts of hydrogen-containing silicone oil; more than or equal to 0.000002 parts of a catalyst; the content of vinyl in the R-vinyl silicone rubber is 0.1-0.5 mol%; the content of Si-H groups in the hydrogen-containing silicone oil is 0.18 to 1.6 mol%; the molar ratio of the Si-H group to the vinyl group is (0.5-20): 1. According to the invention, methyl vinyl silicone rubber, hydrogen-containing silicone oil, a platinum catalyst and other components are taken as a basic prescription of silicone rubber, and a model drug and the silicone rubber are mixed by using an extrusion technology to prepare the hollow skeleton type drug-loaded rod core. Advantages of traditional storage type implants and skeleton type implants are integrated, the production process is simple, the medicine application range is wide, the release amount is stable, and the release amount is large.

Description

Technical Field

[0001] The present invention specifically relates to a hollow skeleton type drug-carrying rod core and a preparation method and application thereof. Background Art

[0002] Since the concept of "sustained-release preparations" was proposed, sustained-release preparations used in contraception, schizophrenia, hormones, anti-tumor and other fields have made great progress, effectively avoiding problems such as surgical injuries and low oral compliance. Sustained-release preparations that can release drugs for a long time, especially subcutaneous implants, have very broad prospects.

[0003] In the prior art, implants can be divided into skeleton-type implants and reservoir-type implants. A skeleton-type implant is a drug preparation that is prepared by mixing a drug with a carrier, using a catalyst, a cross-linking agent, and high temperature, and using a preparation process such as extrusion or molding to prepare it into a drug preparation with certain mechanical properties that can be implanted under the human skin. A reservoir-type implant is generally a drug preparation prepared by directly filling a drug powder or a skeleton-type rod core into a silicone tube.

[0004] Reservoir-type implants have the advantage of stable drug release. They can maintain zero-order stable release within the effective period (which can last for several years), maintain stable blood drug concentration, and have a good therapeutic effect. Since the drug needs to diffuse into the body through the silicone tube, the molecular weight and water solubility of the drug are very high. Only drugs with a molecular weight of less than 800 and a solubility of less than 10 mg / mL can be released. Even if the drug can be released, the dosage is very small, and the daily release amount is generally only a few tens of micrograms. This has great limitations for some drugs with large doses and cannot be used.

[0005] The production process of skeleton-type implants is relatively simple, and they have the advantage of fast drug release. The daily drug release amount is several to dozens of times that of reservoir-type implants. However, their release is not smooth, and the drug release rate will gradually decrease, resulting in unstable blood drug concentrations and even failure to produce drug effects. Summary of the invention

[0006] The technical problem to be solved by the present invention is to overcome the defects of the prior art reservoir-type implants in that they have high requirements on the molecular weight and solubility of drugs, have a small release dose, and cannot meet the needs of large-dose drugs, and the defects of the skeleton-type implants in that they are unstable in drug release, cause fluctuations in blood drug concentrations, produce poisoning phenomena, or have no therapeutic effect, and provide a hollow drug-loaded rod core and a preparation method and application thereof.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] The present invention provides a hollow skeleton type drug-carrying rod core, wherein the raw material composition thereof comprises the following components in parts by weight:

[0009] Active pharmaceutical ingredient: 1-1000 parts;

[0010] R-vinyl silicone rubber: 100 parts;

[0011] Hydrogenated silicone oil: 0.45-20 parts;

[0012] Catalyst: ≥ 0.000002 parts;

[0013] in:

[0014] The R in the R-vinyl silicone rubber is a substituted or unsubstituted C1-C5 straight-chain alkane or branched alkane, a substituted or unsubstituted C6-C 20 Aromatics;

[0015] The content of vinyl in the R-vinyl silicone rubber is 0.1-0.5 mol%;

[0016] The content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol%;

[0017] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):1.

[0018] In the present invention, the dosage of the pharmaceutically active ingredient may be 1-800 parts, for example, 10 parts, 30 parts, 50 parts, 60 parts, 100 parts, 120 parts, 150 parts, 250 parts, 500 parts or 600 parts.

[0019] In the present invention, R in the R-vinyl silicone rubber may be a substituted or unsubstituted C1-C5 straight-chain alkane, such as a methyl group.

[0020] When the R is a methyl group, the R-vinyl silicone rubber is a methyl vinyl silicone rubber.

[0021] The methyl vinyl silicone rubber may be conventional methyl vinyl silicone rubber in the art, for example, methyl vinyl silicone rubber having a relative molecular weight of 100,000-800,000 g / mol.

[0022] In the present invention, the vinyl content in the R-vinyl silicone rubber is preferably 0.17-0.23 mol%, for example, 0.17 mol%, 0.18 mol%, 0.19 mol%, 0.20 mol%, 0.22 mol% or 0.23 mol%.

[0023] In the present invention, the hydrogen-containing silicone oil may be conventional hydrogen-containing silicone oil in the art, such as hydrogen-containing silicone oil purchased from Guangdong Guiye New Material Technology Co., Ltd.

[0024] In the present invention, the amount of the hydrogen-containing silicone oil can be 0.5-20 parts, preferably 1.2-6.3 parts, for example 1.33 parts, 2 parts, 2.67 parts, 3 parts, 3.56 parts or 4.44 parts.

[0025] In the present invention, the content of Si-H groups (hydrogen content) in the hydrogen-containing silicone oil is preferably 0.5-1.5 mol%, such as 0.75 mol%, 0.8 mol%, 1.0 mol% or 1.2 mol%.

[0026] In the present invention, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is preferably (0.8-20):1, for example, 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 3.0:1, 4:1, 4.5:1, 5:1, 8:1, 10:1 or 15:1, preferably (3-8):1 or (3-6):1.

[0027] In the present invention, optionally, the raw material composition further comprises an inhibitor. The inhibitor may be a conventional inhibitor in the art capable of inhibiting the addition reaction between R-vinyl silicone rubber and hydrogen-containing silicone oil at room temperature, such as acetylenic alcohol compounds, nitrogen-containing compounds or organic peroxides, such as methyl butynol, and 2-methyl-3-butyn-2-ol.

[0028] In the present invention, the dosage of the inhibitor can be 0.000002-1 part, preferably 0.03-5 parts, more preferably 0.1-2.0 parts, such as 0.3-1.0 parts, and for example 0.3 parts, 0.5 parts, 0.7 parts, 0.9 parts or 0.98 parts.

[0029] In the present invention, the catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between R-vinyl silicone rubber and hydrogen-containing silicone oil, such as a rhodium catalyst, a palladium catalyst or a platinum catalyst, preferably a platinum catalyst.

[0030] The concentration of platinum in the platinum catalyst may be 10000 ppm, which means that the mass concentration of platinum in the platinum catalyst is 10000 parts per million.

[0031] In the present invention, the amount of the catalyst may be 0.000002-0.5 parts, such as 0.000005 parts, 0.00001 parts, 0.00002 parts, 0.00003 parts, 0.1 parts, 0.2 parts, 0.21 parts, 0.25 parts or 0.3 parts, preferably 0.03-0.3 parts, more preferably 0.1-0.3 parts.

[0032] In the present invention, the vulcanization principle of the two-component addition-type silicone rubber is as follows: the two-component addition-type room temperature vulcanized silicone rubber, for example, is based on vinyl polydimethylsiloxane as a polymer and hydrogen-containing silicone oil as a cross-linking agent. Under the catalytic action of a catalyst (such as a platinum catalyst), the vinyl group and the hydrogen group undergo a silylation reaction to form a cross-linked network structure, and the cross-linked structure can control the release of drugs. The reaction formula is shown below.

[0033]

[0034] After mixing with crosslinking agent and catalyst, raw rubber can react at room temperature, but the mixing and processing of rubber materials require a certain amount of time. If the reactants are cured in advance during operation, the desired shape and properties cannot be obtained. This is especially true for addition-type silicone rubber. Therefore, it is generally required that the catalytic reaction has almost no effect before vulcanization (mixing at room temperature), and reacts rapidly when the vulcanization temperature is reached. The method of inhibiting the reaction is usually to add inhibitors. Inhibitors can form a certain form of complex with platinum catalysts. Effective inhibitors can be placed with rubber materials for a considerable period of time, and can only be vulcanized when heated to a certain vulcanization temperature. Commonly used are acetylenic alcohol compounds, nitrogen-containing compounds, organic peroxides, etc. with good compatibility.

[0035] In the present invention, the active pharmaceutical ingredient is not particularly limited, and may be a conventional sustained-release pharmaceutical ingredient in the art that requires long-term drug release, such as drugs used in the fields of contraception, schizophrenia, hormones, and anti-tumor.

[0036] 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.

[0037] 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 (with water as solvent) and a drug molecular weight greater than 800 Da, preferably including an active drug with a drug solubility of >30 mg / mL (with water as solvent) and a drug molecular weight >800 Da, such as one or more of exenatide, semaglutide, Centella asiatica glycosides and human growth hormone.

[0038] 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 (with water as solvent) and a drug molecular weight of ≤800 Da, preferably including an active drug with a drug solubility of >30 mg / mL (with water as solvent) and a drug molecular weight of ≤800 Da, such as metformin hydrochloride and / or doxorubicin hydrochloride.

[0039] Among them, the macromolecular drug with poor solubility can be an active drug with a conventional drug solubility of ≤10 mg / mL (with water as solvent) and a drug molecular weight of >800 Da in the art, preferably including an active drug with a drug solubility of ≤5 mg / mL (with water as solvent) and a drug molecular weight of >800 Da, such as one or more of bovine insulin, paclitaxel and levothyroxine sodium.

[0040] Among them, the small molecule drug with poor solubility can be an active drug with a conventional drug solubility of ≤10 mg / mL (with water as solvent) and a drug molecular weight of ≤800 Da in the art, preferably including an active drug with a drug solubility of ≤5 mg / mL (with water as solvent) and a drug molecular weight of ≤800 Da, such as one or more of estradiol, gestodene, meloxicam, ganciclovir, puerarin and paliperidone.

[0041] In some preferred embodiments of the present invention, the raw material composition of the hollow skeleton type rod core may include the following components in parts by weight:

[0042]

[0043]

[0044] In some preferred embodiments of the present invention, the raw material composition of the hollow skeleton type rod core may include the following components in parts by weight:

[0045]

[0046] In the present invention, the ratio of the outer diameter to the inner diameter of the hollow skeleton drug-loaded rod core can be 1.5-50:1, for example, 2.14:1, 3:1, 4:1, 5:1, 8:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1 or 40:1.

[0047] In the present invention, the outer diameter of the hollow skeleton-type drug-loaded rod core may be 1 mm-10 mm, preferably 2.0 mm, 3.0 mm, 4 mm or 5 mm.

[0048] In the present invention, the inner diameter of the hollow skeleton drug-loaded rod core may be 0.1 mm-4.0 mm, preferably 0.40 mm-2.0 mm, for example 0.4 mm, 0.6 mm, 0.8 mm, 1.0 mm, 1.2 mm, 1.4 mm, 1.6 mm or 2.0 mm.

[0049] In a preferred embodiment, the outer diameter of the hollow skeleton drug-loaded rod core may be 3 mm, and the inner diameter may be 0.6-1.4 mm, 0.6 mm, 1.0 mm or 1.4 mm.

[0050] In some preferred embodiments of the present invention, the specifications of the hollow skeleton type stick core are shown in the following table, and the pharmaceutical active ingredient is preferably paliperidone;

[0051] serial number Rod core outer diameter (mm) Rod core inner diameter (mm) No. 5-1 3.00 0.60 No. 5-2 3.00 1.00 No. 5-3 3.00 1.40

[0052] The present invention also provides a method for preparing a hollow skeleton-type drug-loaded rod core, which comprises the following method:

[0053] S1: dividing the R-vinyl silicone rubber into component A1 and component B1;

[0054] When the raw material composition contains an inhibitor, the component A1, the hydrogen-containing silicone oil and the inhibitor are mixed to obtain component A2; the component B1 and the catalyst are mixed to obtain component B2;

[0055] S2: mixing the component A2 and the component B2 to obtain a mixed rubber;

[0056] S3: mixing the mixed rubber and the active ingredient of the drug to obtain drug-loaded silica gel;

[0057] S4: The drug-loaded silica gel is extruded and vulcanized to obtain a hollow skeleton-type drug-loaded rod core.

[0058] In S1, the R-vinyl silicone rubber can be pretreated by conventional methods in the art, such as drying at 30-60° C. (eg, 40° C.) for 1-24 h (eg, 12 h) for later use.

[0059] In S1, the preparation method of the component A1 or the component B1 can be conventional in the art. Generally, the components are mixed in an open mill and then thinly passed 4-6 times and discharged in the form of flakes.

[0060] In S2, the step of mixing the component A2 and the component B2 may include the following steps: putting the component A2 and the component B2 in an open mixing mill at a weight ratio of 1:1 and mixing them thinly for 4-6 times, so that the B1 and B2 component rubbers are fully mixed and uniformly formed into a mixed rubber.

[0061] In S3, the step of mixing the rubber compound and the active pharmaceutical ingredient may include the following steps: putting the rubber compound and the active pharmaceutical ingredient into an open mixer for mixing, so that the rubber compound and the active pharmaceutical ingredient are fully mixed and uniformly formed into drug-loaded silica gel. The drug-loaded silica gel may be cut into strips.

[0062] In S4, the extrusion is generally performed in a screw extruder.

[0063] In S4, during the extrusion, the screw speed of the extruder may be 1-15 r·min -1 , for example 4r·min -1or 6 r·min -1 .

[0064] In S4, during the extrusion, the die diameter used is preferably 1-10 mm, for example, 2 mm, 2.96 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm.

[0065] In S4, during the extrusion, the diameter of the mandrel used is preferably 0.1-4 mm, such as 0.58 mm, 0.8 mm, 0.97 mm, 1.2 mm or 1.38 mm.

[0066] In S4, the vulcanization is generally performed in an oven.

[0067] In S4, the vulcanization temperature may be 25-120°C, preferably 60-90°C, for example 30°C, 50°C, 60°C, 65°C, 70°C, 80°C, 90°C, 100°C or 120°C.

[0068] In S4, the vulcanization time may be 10-200 min, preferably 10-60 min, for example 10 min, 20 min, 30 min, 40 min or 50 min.

[0069] The present invention also provides an application of the hollow skeleton-type drug-loaded rod core as a release rate regulating medium in a sustained-release or controlled-release preparation.

[0070] In the present invention, the vinyl content in the R-vinyl silicone rubber refers to the molar percentage, and the molar percentage of vinyl refers to the number of moles of vinyl in every 100 moles of R-vinyl silicone rubber.

[0071] In the present invention, the hydrogen content in the hydrogen-containing silicone oil refers to the mole percentage, and the mole percentage of hydrogen content refers to the number of moles of hydrogen in every 100 moles of the hydrogen-containing silicone oil.

[0072] In the present invention, PHR refers to the mass fraction of each specific component per 100 mass fractions of R-vinyl silicone rubber (eg, methyl vinyl silicone rubber).

[0073] In the present invention, the room temperature refers to 25°C + 5℃.

[0074] 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.

[0075] The reagents and raw materials used in the present invention are commercially available.

[0076] The positive and progressive effects of the present invention are:

[0077] The present invention uses R-vinyl silicone rubber, hydrogen-containing silicone oil, catalyst and other components as the basic formula of silicone rubber, and uses extrusion technology to mix the model drug with silicone rubber to form a hollow skeleton-type drug-loaded rod core. It concentrates the advantages of traditional reservoir-type implants and skeleton-type implants, as follows:

[0078] ①Simple production process: basically the same as the production process of skeleton-type implants, reducing production links and saving costs;

[0079] ② Wide range of drug applications: Applicable to all drugs, not affected by drug molecular weight, solubility, physicochemical properties, particle size, crystal form, etc.; active ingredients with molecular weight > 800Da, or molecular weight ≤ 800Da; and active ingredients with solubility > 10mg / mL or solubility ≤ 10mg / mL can all be applied;

[0080] ③Stable release: Reducing the release rate can achieve zero-order release, stable blood drug concentration, definite efficacy, and meet clinical needs;

[0081] ④ Large release amount: The drug release area is increased, the drug release on the inner and outer surfaces is achieved, and the drug release rate is increased. The released dose is several times that of traditional skeleton-type implants and dozens to hundreds of times that of reservoir-type implants. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1 The skeleton-type rod core prepared in Comparative Example 1 ( Figure 1 Left) and the hollow skeleton type rod core prepared in Example 1-1 ( Figure 1 right) photo.

[0083] Figure 2 1 and 2 are the in vitro release curves of the paliperidone hollow skeleton core of Examples (5-1) to (5-3).

[0084] Figure 3 The in vitro release curves of the paliperidone skeleton stick core of Comparative Example 1 and the paliperidone hollow skeleton stick core of Example 5-3 for 150 days

[0085] Figure 4 This is the 150-day in vitro release curve of the estradiol skeleton type stick core of Comparative Example 2 and the estradiol hollow skeleton type stick core of Example 6.

[0086] Figure 5 The in vitro release curves of the gestodene skeleton type stick core of comparative example 3 and the gestodene hollow skeleton type stick core of example 7 for 150 days are shown.

[0087] Figure 6 The in vitro release curves of the levothyroxine sodium skeleton-type stick core of Comparative Example 4 and the levothyroxine sodium skeleton hollow skeleton-type stick core of Example 8 for 150 days are shown.

[0088] Figure 7 These are the in vitro release curves of the metformin hydrochloride skeleton-type stick core of Comparative Example 5 and the metformin hydrochloride hollow skeleton-type stick core of Example 9.

[0089] Figure 8 The in vitro release curves of the paclitaxel skeleton-type stick core of Comparative Example 6 and the paclitaxel hollow skeleton-type stick core of Example 10 are shown.

[0090] Fig. 9 The in vitro release curves of the Centella asiatica total glycosides skeleton type stick core of Comparative Example 7 and the Centella asiatica total glycosides hollow skeleton type stick core of Example 11. DETAILED DESCRIPTION

[0091] 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.

[0092] The sources of the components in the embodiments and comparative examples are shown in Table 1.

[0093] Table 1

[0094]

[0095]

[0096] Example 1-4 Paliperidone hollow skeleton rod core

[0097] Hollow skeleton core rod formulation and process investigation

[0098] (1) Using tensile strength, elongation at break and tear strength as evaluation indicators, the effects of catalyst dosage, hydrogen-containing silicone oil dosage, vulcanization temperature and vulcanization time on the mechanical properties of the skeleton-type rod core were studied.

[0099] Tensile strength (Ts) is the maximum tensile stress to which the specimen is subjected until it breaks, representing the material's maximum resistance to uniform plastic deformation and the maximum resistance of the rod core to external damage. Elongation at break (Eb) refers to the ratio of the elongated portion of the specimen to its original length when it breaks, representing the deformation range of the specimen and the deformation range that the rod core can accept before breaking. Tear strength (T) refers to the strength required to tear the specimen, representing the rod core's ability to resist tearing.

[0100] (2) Mechanical properties determination method:

[0101] The prepared skeleton rod core is placed symmetrically on the upper and lower clamps of the servo system tensile machine, the clamp distance is set to 50 mm, and the elongation test device is prepared. The tensile rate of the sample is set to 200 mm min -1 , start the tensile machine. Record the maximum tensile stress during the stretching process, the length of the sample when stretched to fracture, and the force required to tear the sample. Calculate the elongation at break, tensile strength, and tear strength of the sample according to the following formula.

[0102] Elongation at break (%) E b =100(L b -L0) / L0

[0103] L b - gauge length of the specimen at fracture, mm, L0 - initial gauge length of the specimen, mm.

[0104] Tensile strength (MPa) Ts = Fm / Wt

[0105] Fm - maximum force recorded, W - width of the narrow part of the cutter, mm, t - thickness of the length of the specimen.

[0106] Tear strength (KN / m) T = F / t

[0107] F is the maximum force required to tear the sample, t is the thickness of the sample (mm).

[0108] Example 1 Investigation of Catalyst Dosage

[0109] 1. The basic formula and mechanical properties of the hollow skeleton rod core are shown in Table 2.

[0110] Table 2

[0111]

[0112]

[0113] Note: PHR (parts per hundreds of rubber) indicates the number of parts of the component per 100 parts of methyl vinyl silicone rubber; ppm (parts per million) is parts per million, indicating the mass concentration of platinum in the platinum catalyst.

[0114] 2. Preparation process of hollow skeleton rod core:

[0115] (1) Drying pretreatment of raw rubber: Dry the methyl vinyl silicone rubber raw rubber at 40°C for 12 hours for later use.

[0116] (2) Preparation of component A and B rubber: Take the prescribed amount of R-vinyl silicone rubber and divide it equally into two components A1 and B1. Add hydrogen-containing silicone oil and inhibitor to component A1, mix it evenly in an open mill, pass it through several times and unload it in the form of thin slices to obtain component A2. Add platinum catalyst to component B1, mix it evenly in an open mill, pass it through several times and unload it in the form of thin slices to obtain component B2.

[0117] (3) Preparation of rubber compound: The prepared A2 and B2 component flakes are put into an open mixer at a ratio of 1:1 and mixed for 4 to 6 times to ensure that the A2 and B2 component rubbers are fully mixed and uniformly formed into a rubber compound.

[0118] (4) Preparation of drug-loaded silica gel: Paliperidone and the mixed rubber are mixed evenly on an open mixer to prepare drug-loaded silica gel, which is then cut into strips.

[0119] (5) Extrusion of hollow skeleton rod core: Install a 2.96 mm diameter die, a 1.38 mm diameter core die, and set the extruder screw speed to 4 r / min. -1 The cut drug-loaded silicone strips are put into the extruder, and the drug-loaded silicone is continuously extruded through the die mouth into a hollow skeleton-type rod core under the push of the screw.

[0120] Among them, the size of the hollow skeleton type rod core: the outer diameter of the hollow skeleton type rod core is determined by the diameter of the mouth die, and the inner diameter is determined by the diameter of the core die.

[0121] (6) Vulcanization of the hollow skeleton rod core: After extrusion, the rod core is placed in an oven and vulcanized at 80°C for 30 minutes to form an elastomer.

[0122] 3. The results show that as the amount of catalyst increases, the mechanical index of the rod core is first significantly enhanced and then slightly decreased, and the best is achieved when the catalyst dosage is 0.21PHR. During the experiment, it was found that when the catalyst dosage increased to 0.25PHR and 0.3PHR, due to excessive dosage, the rubber material was slightly hard during the drug-rubber mixing and drug core extrusion process, resulting in rough extrusion of the rod core and decreased mechanical properties. Therefore, the catalyst dosage of 10000ppm can be 0.1-0.3PHR, and 0.21PHR is the most preferred.

[0123] Example 2 Investigation of the amount of hydrogen-containing silicone oil used

[0124] 1. The basic formula and mechanical properties of the hollow skeleton rod core are shown in Table 3.

[0125] 2. The preparation process of the fixed hollow skeleton type rod core is the same as that in Example 1.

[0126] Table 3

[0127]

[0128] 3. The results show that as the amount of hydrogenated silicone oil increases, the mechanical properties of the rod core gradually increase. Generally, in the addition reaction of addition-type silicone rubber, the molar ratio of hydrogenated silicone oil to silicone rubber vinyl is generally sufficient between 1.2 and 1.5. However, for the rod core after drug-gel mixing, the presence of a large amount of drug in silicone rubber will hinder the contact between the hydrogenated silicone oil silane group and the vinyl group, resulting in incomplete reaction. Therefore, it is necessary to continue to increase the molar ratio to make the excess of hydrogenated silicone oil more and more effective hydrogenated silicone oil that can participate in the addition reaction, so that the final reaction can be complete and the drug core can reach the optimal vulcanization state. In this experiment, the molar ratio of hydrogenated silicone oil is selected to be 2.0-6.0.

[0129] Example 3 Investigation of vulcanization temperature

[0130] 1. The basic formula for fixing the hollow skeleton type rod core is that of Example 2-3.

[0131] 2. The preparation process of the hollow skeleton type rod core is the same as that of Example 1, except that:

[0132] (5) Extrusion of rod core: Install a 2.96 mm diameter die, a 1.38 mm inner diameter core die, and set the extruder screw speed to 6 r / min -1 The cut drug-loaded silicone strips are put into the extruder, and the drug-loaded silicone is continuously extruded into a rod core through the die mouth under the push of the screw.

[0133] (6) Vulcanization of the rod core: After extrusion, the rod core is placed in an oven and vulcanized (the vulcanization process and mechanical property data are shown in Table 4) into an elastomer.

[0134] Table 4

[0135]

[0136]

[0137] 3. The results show that when the vulcanization temperature is 30-60℃, the mechanical properties are poor and the vulcanization effect is not good. When the vulcanization temperature is 60℃-90℃, the mechanical properties of the core first improve and then deteriorate, and continue to decline at 90℃-120℃. Therefore, considering the mechanical properties of the core and the thermal stability of the drug, the vulcanization temperature is selected to be 60-90℃, preferably 65-90℃.

[0138] Example 4 Investigation of curing time

[0139] 1. The basic formula for fixing the hollow skeleton type rod core is that of Example 2-3.

[0140] 2. The preparation process of the hollow skeleton type rod core is the same as that of Example 1, except that:

[0141] (6) Vulcanization of the rod core: After extrusion, the rod core is placed in an oven and vulcanized (the vulcanization process and mechanical property data are shown in Table 5) into an elastomer.

[0142] Table 5

[0143] name Example 4-1 Example 4-2 Example 4-3 Example 4-4 Embodiment 4-5 Vulcanization time min 10 20 30 40 50 Vulcanization temperature ℃ 80 80 80 80 80 Tensile strength(MPa) 1.88 2.01 2.34 1.93 1.88 Elongation at break (%) 125 143 158 137 132 Tear strength (KN / m) 1.32 1.45 1.48 1.41 1.38

[0144] 3. The results show that when the curing time is 30 minutes, the core rod reaches the best mechanical index, while when the curing time is 40 minutes and 50 minutes, the mechanical properties of the core rod do not increase with the increase of curing time, indicating that the core rod has reached the best curing state when the curing temperature is 80°C and 30 minutes. The curing time of the present invention can be 10-60 minutes.

[0145] In summary, the final formula and process of the hollow skeleton rod core are: paliperidone 100PHR; methyl vinyl silicone rubber with 0.18% vinyl content 100PHR; hydrogen-containing silicone oil with 0.75mol% hydrogen content 4.4PHR; the molar ratio of Si-H group in hydrogen-containing silicone oil to vinyl group in methyl vinyl silicone rubber is 5:1; hydrogen content of hydrogen-containing silicone oil is 0.75mol%; platinum catalyst with a platinum concentration of 10000ppm 0.21PHR; 2-methyl-3-butyn-2-ol 0.98PHR; vulcanization temperature 80℃; vulcanization time 30min. Unless otherwise specified, the basic formula and process of the following hollow skeleton rod core are carried out according to this.

[0146] Example 5 Paliperidone hollow skeleton core

[0147] 1. Basic formula and preparation process of hollow skeleton rod core

[0148] Except for the size of the hollow skeleton rod core, the basic formula and preparation process are the same as the optimal formula and process obtained in Example 1-4. The extruder screw speed is set to 6r·min -1 .

[0149] 2. Investigation of the extrusion size of hollow skeleton rod core

[0150] 2.1 Effect of die diameter and core die diameter on the core diameter of hollow skeleton rod

[0151] The effects of the die and core mold with different diameters on the diameter of the hollow skeleton rod core were investigated. The die determines the outer diameter of the hollow skeleton rod core, and the core mold determines the inner diameter of the hollow skeleton rod core. Different die and core molds were used to prepare hollow skeleton rod cores of different sizes, as shown in Table 6.

[0152] Table 6 Hollow skeleton rod cores of different sizes

[0153]

[0154] Experimental results: After the drug-loaded rod core passes through the mouth die and the core die, the actual diameter is slightly larger than the diameter of the mold. Mouth dies and core molds of different diameters can be matched according to actual needs to prepare a hollow skeleton-type rod core with an outer diameter of 1.8-6mm and an inner diameter of 0.4-2mm.

[0155] Unless otherwise specified, a 2.96 mm die and a 1.38 mm core die were selected in the following examples, and a hollow skeleton-type rod core with an outer diameter of 3 mm and an inner diameter of 1.40 mm was finally prepared.

[0156] Comparative Example 1 Paliperidone skeleton type stick core (solid skeleton type stick core)

[0157] 1. The basic formula is the same as that of the hollow skeleton type rod core in Example 5-3.

[0158] 2. Preparation process of skeleton type rod core

[0159] Steps (1) to (4) are the same as in Example 5-3;

[0160] (5) Extrusion of the rod core: Install a die with a diameter of 2.96 mm and set the extruder screw speed to 6 r / min -1 , put the cut drug-loaded silicone strips into the extruder, and the drug-loaded silicone is continuously extruded into a rod core through the die mouth under the push of the screw. The diameter of the skeleton-type rod core is 3mm. Among them, the size of the rod core: the diameter of the skeleton-type rod core is determined by the die diameter.

[0161] (6) Vulcanization of the rod core: After extrusion, the rod core is placed in an oven and vulcanized at 80°C for 30 minutes to form an elastomer.

[0162] Figure 1 The skeleton-type rod core prepared in Comparative Example 1 ( Figure 1 Left) and the hollow skeleton rod core prepared in Example 1-1 ( Figure 1 right).

[0163] Example 6 Estradiol Hollow Skeleton Rod Core

[0164] 1. Basic prescription: Same as the basic prescription of Example 5-3, except that the drug is replaced with estradiol in equal amounts.

[0165] 2. The preparation process is the same as that of Example 5-3 except that the vulcanization temperature is 70°C and the vulcanization time is 50 min.

[0166] Comparative Example 2 Estradiol skeleton type stick core

[0167] 1. The basic recipe is the same as that of Example 6.

[0168] 2. The preparation process is the same as that of Comparative Example 1 except that the vulcanization temperature is 70° C. and the vulcanization time is 50 min.

[0169] Example 7 Gestodene Hollow Skeleton Rod Core

[0170] 1. Basic formula: replace the drug with gestodene in equal amounts, the molar ratio of hydrogenated silicone oil to vinyl in methyl vinyl silicone rubber is 4.5:1, and the rest is the same as Example 5-3.

[0171] 2. The preparation process is the same as that of Example 5-3 except that the vulcanization temperature is 90°C and the vulcanization time is 50 min.

[0172] Comparative Example 3: Gestodene skeleton type stick core

[0173] 1. The basic recipe is the same as that of Example 7.

[0174] 2. The preparation process is the same as that of Comparative Example 1 except that the vulcanization temperature is 90° C. and the vulcanization time is 50 min.

[0175] Example 8 Levothyroxine Sodium Hollow Skeleton Rod Core

[0176] 1. Basic prescription: replace the drug with levothyroxine sodium in equal amounts, the molar ratio of hydrogenated silicone oil to vinyl in methyl vinyl silicone rubber is 3:1, and the rest is the same as Example 5-3.

[0177] 2. The preparation process is the same as that of Example 5-3 except that the vulcanization temperature is 50°C.

[0178] Comparative Example 4 Levothyroxine Sodium Skeleton-Type Rod Core

[0179] 1. The basic recipe is the same as that of Example 8.

[0180] 2. Preparation process The vulcanization temperature is 50°C, and the rest is the same as Comparative Example 1.

[0181] Example 9 Metformin hydrochloride hollow skeleton stick core

[0182] 1. The amount of metformin hydrochloride added in the basic formula was adjusted to 30 PHR, and the rest was the same as Example 5-3.

[0183] 2. The preparation process is the same as that of Example 5-3.

[0184] Comparative Example 5: Metformin hydrochloride skeleton stick core

[0185] 1. The basic recipe is the same as that of Example 9.

[0186] 2. The preparation process is the same as that of Comparative Example 1.

[0187] Example 10 Paclitaxel Hollow Skeleton Rod Core

[0188] 1. Basic prescription: The amount of paclitaxel added was adjusted to 80 PHR, and the rest was the same as Example 5-3.

[0189] 2. The preparation process is the same as Example 5-3 except that the vulcanization temperature is 75°C.

[0190] Comparative Example 6 Paclitaxel skeleton core

[0191] 1. The basic recipe is the same as that of Example 10.

[0192] 2. The preparation process is the same as that of Comparative Example 1 except that the vulcanization temperature is 75°C.

[0193] Example 11 Centella asiatica total glycosides hollow skeleton stick core

[0194] 1. Basic prescription: The amount of total glycosides of Centella asiatica added was adjusted to 40 PHR, and the rest was the same as Example 5-3

[0195] 2. The preparation process is the same as that in Example 1.

[0196] Comparative Example 7 Centella asiatica total glycosides skeleton stick core

[0197] 1. The basic recipe is the same as that of Example 11.

[0198] 2. The preparation process is the same as that of Comparative Example 1.

[0199] Effect Example In vitro release study of different preparations

[0200] 1. Chromatographic conditions for in vitro release of paliperidone: Chromatographic column: C18 chromatographic column (4.6×100 mm, 2.7 μm); mobile phase: methanol: water (45:55, v / v) (pH adjusted to 3 with phosphoric acid); column temperature: 35°C; detection wavelength: 280 nm; flow rate: 1.0 mL·min -1 ; Injection volume: 20μL.

[0201] 2. Chromatographic conditions for in vitro release of estradiol: Chromatographic column: C18 column (250 mm × 4 mm, 5 μm); mobile phase: acetonitrile-water (55:45, v / v); column temperature: 25 °C; detection wavelength: 202 nm; flow rate: 0.8 mL min -1 ; Injection volume: 20μL.

[0202] 3. Chromatographic conditions for in vitro release of gestodene: Chromatographic column: C18 chromatographic column (4.6 mm × 250 mm, 5 μm); mobile phase: methanol: water (80:20, v / v); column temperature: 30 °C; detection wavelength: 239 nm; flow rate: 1.0 mL min -1 ; Injection volume: 20μL.

[0203] 4. Chromatographic conditions for in vitro release of levothyroxine sodium: Chromatographic column: SinoDetect C18 column (4.6*250mm, 5μm); Mobile phase: acetonitrile-0.1% TFA (50:50, v / v); Column temperature: 30°C; Detection wavelength: 225nm; Flow rate: 0.8mL·min -1 ; Injection volume: 20μL.

[0204] 5. In vitro release chromatographic conditions of metformin hydrochloride: Chromatographic column: C18 chromatographic column (4.6×100 mm, 2.7 μm); mobile phase: methanol: water (60:40, v / v) (pH adjusted to 3 with phosphoric acid); column temperature: 40°C; detection wavelength: 218 nm; flow rate: 1.0 mL·min -1 ; Injection volume: 20μL.

[0205] 6. Chromatographic conditions for in vitro release of paclitaxel: Chromatographic column: C18 chromatographic column (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile: water (45:55, v / v); column temperature: 35 °C; detection wavelength: 227 nm; flow rate: 1.0 mL min -1 ; Injection volume: 20μL.

[0206] 7. Chromatographic conditions for in vitro release of total glycosides from Centella asiatica: Chromatographic column: C18 chromatographic column (4.6 mm × 250 mm, 5 μm) methanol: water (60:40, v / v); column temperature: 35 °C; detection wavelength: 276 nm; flow rate: 1.0 mL min -1 ; Injection volume: 20μL.

[0207] 8. In vitro release test method

[0208] Using the horizontal oscillation method, take a stick core and fix the two ends of the core to the bottom and wall of a 100mL conical flask with a silicone adhesive (to prevent the stick core from floating on the liquid surface and causing inaccurate release results). After adhesion, leave it for 12 hours to allow the adhesive to cure completely. Accurately measure 100mL of distilled water as the release medium and inject it into the conical flask. Place the conical flask in a constant temperature air shaker and shake it. The temperature is set to 37°C and the amplitude is 100r·min. -1 The medium was replaced with an equal volume every 1 day.

[0209] 9 In vitro release results

[0210] 9.1 In vitro release results of paliperidone hollow skeleton core with different outer diameter and inner diameter ratios

[0211] Figure 2 1 and 2 are the in vitro release curves of the paliperidone hollow skeleton core of Examples (5-1) to (5-3).

[0212] Table 7 In vitro release results of paliperidone hollow skeleton core with different outer diameter and inner diameter ratios

[0213]

[0214] It can be seen from the above table that the release speeds are different for different ratios of outer diameter to inner diameter. When the outer diameter is constant, the smaller the inner diameter is, the less water permeates and the slower the release speed is. Under the condition of ensuring good mechanical properties and a faster release speed, the size of the hollow skeleton rod core in the embodiment of the present invention is selected to be 3mm in outer diameter and 1.40mm in inner diameter.

[0215] 9.2 Comparison of in vitro release results of paliperidone

[0216] Figure 3 The in vitro release curves of the paliperidone skeleton stick core of comparative example 1 and the paliperidone hollow skeleton stick core of example 5-3 for 150 days are shown. It can be seen that after the paliperidone skeleton stick core is prepared into a hollow skeleton stick core, the drug release rate is about 3-4 times that of the original one.

[0217] Table 8 150-day in vitro release data of paliperidone skeleton core

[0218]

[0219]

[0220] Table 9 150-day in vitro release data of paliperidone hollow skeleton core

[0221] Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> 1 902.12 5 408.70 55 322.29 105 367.16 10 434.63 60 395.07 110 341.03 15 304.26 65 352.03 115 384.26 20 375.07 70 342.29 120 341.32 25 379.45 75 351.61 125 364.11 30 375.38 80 380.19 130 320.55 35 358.23 85 351.83 135 375.02 40 375.28 90 364.30 140 346.17 45 358.71 95 328.76 145 334.24 50 332.26 100 340.21 150 333.30

[0222] 9.3 Comparison of in vitro release results of estradiol

[0223] Figure 4 The in vitro release curves of the estradiol skeleton stick core of Comparative Example 2 and the estradiol hollow skeleton stick core of Example 6 for 150 days. Figure 4 It can be seen that the release rate of the estradiol skeleton-type stick core prepared into the estradiol hollow skeleton-type stick core is about 4 times that of the original one.

[0224] Table 10 150-day in vitro release data of estradiol skeleton core

[0225]

[0226]

[0227] Table 11 150-day in vitro release data of estradiol hollow skeleton stick core

[0228] Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> 1 562.39 5 542.23 55 502.19 105 517.04 10 589.35 60 533.03 110 533.51 15 639.17 65 517.28 115 517.25 20 598.36 70 526.14 120 526.12 25 559.31 75 523.19 125 523.23 30 520.29 80 526.26 130 526.60 35 559.83 85 521.76 135 516.36 40 520.47 90 518.30 140 515.15 45 519.18 95 517.25 145 518.35 50 510.30 100 510.47 150 513.24

[0229] 9.4 Comparison of in vitro release results of gestodene

[0230] Figure 5 The in vitro release curves of the gestodene skeleton stick core of comparative example 3 and the gestodene hollow skeleton stick core of example 7 for 150 days are shown. Figure 5 It can be seen that the release rate of the gestodene skeleton-type stick core prepared into the gestodene hollow skeleton-type stick core is about 3-4 times that of the original one.

[0231] Table 12 150-day in vitro release data of gestodene skeleton core

[0232]

[0233] Table 13 150-day in vitro release data of gestodene hollow skeleton stick core

[0234]

[0235] 9.5 Comparison of in vitro release results of levothyroxine sodium

[0236] Figure 6 The in vitro release curves of the levothyroxine sodium skeleton-type stick core of comparative example 4 and the levothyroxine sodium skeleton hollow skeleton-type stick core of example 8 for 150 days are shown. Figure 6 It can be seen that the release rate of the levothyroxine sodium skeleton-type stick core prepared into the levothyroxine sodium hollow skeleton-type stick core is about 3-4 times that of the original one.

[0237] Table 14 150-day in vitro release data of levothyroxine sodium skeleton core

[0238] Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> Time (d) <![CDATA[Daily release dose (μg·d -1 ) <!-- 15 -->]]> 1 301.29 5 142.44 55 122.77 105 113.54 10 148.73 60 123.68 110 113.78 15 144.30 65 120.55 115 113.64 20 147.63 70 122.42 120 101.90 25 148.15 75 119.65 125 100.42 30 140.98 80 116.81 130 100.51 35 140.16 85 116.37 135 104.82 40 134.85 90 119.59 140 104.16 45 138.20 95 115.14 145 104.55 50 137.92 100 117.80 150 101.29

[0239] Table 15 150-day in vitro release data of levothyroxine sodium hollow skeleton rod core

[0240]

[0241]

[0242] 9.6 Comparison of in vitro release results of metformin hydrochloride

[0243] Figure 7The in vitro release curves of the metformin hydrochloride skeleton stick core of comparative example 5 and the metformin hydrochloride hollow skeleton stick core of example 9. From the table below, it can be seen that the hollow skeleton stick core can increase its drug release rate by about 4 times and maintain stable drug release.

[0244] Table 16 In vitro release data of metformin hydrochloride skeleton type stick core (Comparative Example 5) and hollow skeleton type stick core (Example 9)

[0245] Time (d) <![CDATA[Daily release dose (mg·d -1 )]]> Time (d) <![CDATA[Example 9 Daily release dose (mg·d -1 )]]> 1 1.31 1 2.19 5 0.65 5 1.08 10 0.43 10 1.38 15 0.19 15 0.61 20 0.23 20 0.64 25 0.15 25 0.68 30 0.14 30 0.57

[0246] 9.7 Comparison of in vitro release results of paclitaxel

[0247] Figure 8 The in vitro release curves of the paclitaxel skeleton-type stick core of comparative example 6 and the paclitaxel hollow skeleton-type stick core of example 10 are shown. Figure 8 It can be seen that the release rate of the paclitaxel hollow skeleton type stick core prepared from the paclitaxel skeleton type stick core is about 3-4 times that of the original one.

[0248] Table 17 150-day in vitro release data of paclitaxel skeleton core

[0249]

[0250]

[0251] Table 18 150-day in vitro release data of paclitaxel hollow skeleton core

[0252] Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> Time (d) <![CDATA[Daily release dose (μg·d -1 )]]> 1 435.79 5 235.48 55 248.96 105 239.07 10 259.55 60 249.71 110 237.75 15 236.34 65 249.65 115 237.41 20 228.42 70 249.20 120 229.53 25 242.07 75 247.25 125 228.60 30 233.21 80 248.71 130 226.67 35 249.88 85 237.54 135 231.51 40 247.19 90 237.38 140 227.85 45 245.66 95 238.06 145 225.96 50 247.04 100 239.82 150 225.37

[0253] 9.8 Comparison of in vitro release results of total Centella asiatica glycosides

[0254] Fig. 9 The in vitro release curves of the Centella asiatica total glycoside skeleton type stick core of comparative example 7 and the Centella asiatica total glycoside hollow skeleton type stick core of example 11. From the table below, it can be seen that the hollow skeleton type stick core is suitable for active drugs with a concentration of >30 mg / mL (with water as solvent) and a molecular weight greater than 800 Da, and can increase its release rate by about 3-4 times and maintain stable release.

[0255] Table 19 In vitro release data of Centella asiatica total glycosides skeleton type stick core (Comparative Example 7) and Centella asiatica total glycosides hollow skeleton type stick core (Example 11)

[0256] Time (d) <![CDATA[Daily release dose (mg·d -1 )]]> Time (d) <![CDATA[Example 11 Daily release dose (mg·d -1 )]]> 1 2.31 1 3.62 5 0.83 5 2.53 6 0.86 6 2.48 10 0.85 10 2.51 15 0.69 15 2.40 20 0.63 20 2.43 25 0.49 25 2.29 30 0.52 30 2.38

Claims

1. A hollow skeleton drug-loaded rod core, characterized in that: The raw material composition includes the following components in parts by weight: Active pharmaceutical ingredient: 1-1000 parts; R-vinyl silicone rubber: 100 parts; Hydrogenated silicone oil: 0.45-20 parts; Catalyst: ≥ 0.000002 parts; in: The R in the R-vinyl silicone rubber is a substituted or unsubstituted C1-C5 straight-chain alkane or branched alkane, a substituted or unsubstituted C6-C 20 Aromatics; The content of vinyl in the R-vinyl silicone rubber is 0.1-0.5 mol%; The content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol%; The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):

1.

2. The hollow skeleton drug-loaded rod core according to claim 1, characterized in that: The raw material composition meets one or more of the following conditions: ① The dosage of the active ingredient of the medicine is 1-800 parts; ② The content of vinyl in the R-vinyl silicone rubber is 0.17-0.23 mol%; ③ The amount of the hydrogen-containing silicone oil is 0.5-20 parts; ④ The content of Si-H groups in the hydrogen-containing silicone oil is 0.5-1.5 mol%; ⑤ the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.8-20):1; and, ⑥ The amount of the catalyst used is 0.000002-1 part.

3. The hollow skeleton drug-loaded rod core according to claim 2, characterized in that: The raw material composition meets one or more of the following conditions: ① The dosage of the active ingredient of the medicine is 10 parts, 30 parts, 50 parts, 60 parts, 100 parts, 120 parts, 150 parts, 250 parts, 500 parts or 600 parts; ② The content of vinyl in the R-vinyl silicone rubber is 0.17 mol%, 0.18 mol%, 0.19 mol%, 0.20 mol%, 0.22 mol% or 0.23 mol%; ③ The amount of the hydrogen-containing silicone oil is 1.2-6.3 parts, for example, 1.33 parts, 2 parts, 2.67 parts, 3 parts, 3.56 parts or 4.44 parts; ④ The content of Si-H groups in the hydrogen-containing silicone oil is 0.75 mol%, 0.8 mol%, 1.0 mol% or 1.2 mol%; ⑤ the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 3.0:1, 4:1, 4.5:1, 5:1, 8:1, 10:1 or 15:1, preferably (3-8):1 or (3-6):1; and, ⑥ The amount of the catalyst is 0.000002-0.5 parts, for example 0.000005 parts, 0.00001 parts, 0.00002 parts, 0.00003 parts, 0.1 parts, 0.2 parts, 0.21 parts, 0.25 parts or 0.3 parts; preferably 0.03-0.3 parts, more preferably 0.1-0.3 parts.

4. The hollow skeleton drug-loaded rod core according to claim 1, characterized in that: The raw material composition meets one or more of the following conditions: ① R in the R-vinyl silicone rubber is a substituted or unsubstituted C1-C5 straight chain alkane; When the R is a methyl group, the R-vinyl silicone rubber is a methyl vinyl silicone rubber; Wherein, the methyl vinyl silicone rubber may be a methyl vinyl silicone rubber having a relative molecular weight of 100000-800000 g / mol; ② The catalyst is a rhodium catalyst, a palladium catalyst or a platinum catalyst; Wherein, the concentration of platinum in the platinum catalyst may be 10000 ppm; ③ The raw material composition further includes an inhibitor, which is an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil; The inhibitor may be an acetylenic alcohol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol, and also 2-methyl-3-butyn-2-ol; The inhibitor may be used in an amount of 0.03-5 parts, preferably 0.1-2.0 parts, more preferably 0.3-1.0 parts, such as 0.3 parts, 0.5 parts, 0.7 parts, 0.9 parts or 0.98 parts.

5. The hollow skeleton drug-loaded rod core according to claim 1, characterized in that: The active pharmaceutical ingredient is one or more of a macromolecular drug with good solubility, a small molecule drug with good solubility, a macromolecular drug with poor solubility, and a small molecule drug with poor solubility; Wherein, the macromolecular drug with good solubility is an active drug with water as solvent, drug solubility>10mg / mL, and drug molecular weight>800Da; The small molecule drug with good solubility is an active drug with water as solvent, drug solubility>10mg / mL, and drug molecular weight ≤800Da; The poorly soluble macromolecular drug is an active drug with water as solvent, drug solubility ≤10 mg / mL, and drug molecular weight >800 Da; The small molecule drug with poor solubility is an active drug with water as solvent, drug solubility ≤10 mg / mL, and drug molecular weight ≤800 Da.

6. The hollow skeleton drug-loaded rod core according to claim 5, characterized in that: The macromolecular drug with good solubility is an active drug with water as solvent, drug solubility>30 mg / mL, and drug molecular weight>800 Da, such as one or more of exenatide, semaglutide, Centella asiatica glycosides and human growth hormone; The small molecule drug with good solubility is an active drug with water as solvent, drug solubility>30 mg / mL, and drug molecular weight ≤800 Da, such as metformin hydrochloride and / or doxorubicin hydrochloride. The poorly soluble macromolecular drug is an active drug with water as solvent, drug solubility ≤5 mg / mL (with water as solvent), and drug molecular weight >800 Da, such as one or more of bovine insulin, paclitaxel, and levothyroxine sodium; The small molecule drug with poor solubility is an active drug with water as solvent, drug solubility ≤5 mg / mL (with water as solvent), and drug molecular weight ≤800 Da, such as one or more of estradiol, gestodene, meloxicam, ganciclovir, puerarin and paliperidone.

7. The hollow skeleton drug-loaded rod core according to claim 1, characterized in that: The ratio of the outer diameter to the inner diameter of the hollow skeleton drug-loaded rod core is 1.5-50:1, for example, 2.14:1, 3:1, 4:1, 5:1, 8:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1 or 40:1; Alternatively, the outer diameter of the hollow skeleton-type drug-loaded rod core is 1 mm-10 mm, preferably 2.0 mm, 3.0 mm, 4 mm or 5 mm; Alternatively, the inner diameter of the hollow skeleton-type drug-loaded rod core is 0.1 mm-4.0 mm, preferably 0.40 mm-2.0 mm, for example 0.4 mm, 0.6 mm, 0.8 mm, 1.0 mm, 1.2 mm, 1.4 mm, 1.6 mm or 2.0 mm; Preferably, the outer diameter of the hollow skeleton-type drug-loaded rod core is 3 mm, and the inner diameter is 0.6-1.4 mm, 0.6 mm, 1.0 mm or 1.4 mm.

8. A method for preparing a hollow skeleton drug-loaded rod core according to any one of claims 1 to 7, characterized in that: It includes the following methods: S1: dividing the R-vinyl silicone rubber into component A1 and component B1; When the raw material composition contains an inhibitor, the component A1, the hydrogen-containing silicone oil and the inhibitor are mixed to obtain component A2; the component B1 and the catalyst are mixed to obtain component B2; S2: mixing the component A2 and the component B2 to obtain a mixed rubber; S3: mixing the mixed rubber and the active pharmaceutical ingredient to obtain drug-loaded silica gel; S4: The drug-loaded silica gel is extruded and vulcanized to obtain a hollow skeleton-type drug-loaded rod core.

9. The method for preparing the hollow skeleton drug-loaded rod core according to claim 8, characterized in that: The preparation method meets one or more of the following conditions: ① In S1, the R-vinyl silicone rubber is pretreated by the following method: drying at 30-60° C. for 1-24 hours; ② In S1, the preparation method of the component A1 or the component B1 comprises the following steps: mixing the components in an open mill and then thinly passing them 4-6 times; ③ In S2, the step of mixing the component A2 and the component B2 comprises the following steps: putting the component A2 and the component B2 in a weight ratio of 1:1 into an open mixing mill and mixing them thinly for 4-6 times, so that the B1 and B2 component rubbers are fully mixed and uniformly formed into a mixed rubber; ④ In S3, the step of mixing the rubber mix and the active pharmaceutical ingredient comprises the following steps: putting the rubber mix and the active pharmaceutical ingredient into an open mixer for mixing, so that the rubber mix and the active pharmaceutical ingredient are fully mixed and uniformly formed into drug-loaded silica gel; ⑤ In S4, during the extrusion, the screw speed of the extruder is 1-15 r·min -1 , for example 4r·min -1 or 6 r·min -1 ; ⑥ In S4, during the extrusion, the die diameter used is 1-10 mm, for example, 2 mm, 2.96 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm; ⑦ In S4, during the extrusion, the diameter of the core die used is 0.1-4 mm, such as 0.58 mm, 0.8 mm, 0.97 mm, 1.2 mm or 1.38 mm; ⑧ In S4, the vulcanization temperature is 25-120°C, preferably 60-90°C, for example 30°C, 50°C, 60°C, 65°C, 70°C, 80°C, 90°C, 100°C or 120°C; ⑨ In S4, the vulcanization time is 10-200 min, preferably 10-60 min, for example 10 min, 20 min, 30 min, 40 min or 50 min.

10. Use of the hollow skeleton drug-loaded rod core according to any one of claims 1 to 7 as a release rate regulating medium in a sustained-release or controlled-release preparation.

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