Technetium [ 99tc] methylene diphosphonate oral formulation, preparation method therefor, and use thereof

Abstract

The present invention provides a technetium [99Tc] methylene diphosphonate oral formulation, a preparation method therefor, and a use thereof. The oral formulation is prepared by the following raw materials, comprising, in parts by weight, a methylene diphosphonic acid, a reducing agent, a sodium [99Tc] pertechnetium, an adhesive, and a solvent. The adhesive is made of a high molecular polymer material. The oral formulation is prepared by the steps of using the methylene diphosphonic acid, the reducing agent, and the sodium [99Tc] pertechnetium to prepare technetium [99Tc] methylene diphosphonate, timely dissolving technetium [99Tc] methylene diphosphonate in the solvent, and forming a mixed solution with the adhesive for spray drying treatment, wherein the temperature of an air outlet in the spray drying treatment process does not exceed 115°C. By means of the high molecular polymer material, and the timing of spray drying and temperature control, the technetium [99Tc] methylene diphosphonate oral formulation prepared in the present application has a good bioavailability, so that the gastrointestinal irritation can be relieved and the use compliance of a patient can be improved while a same drug effect is achieved, thereby achieving an unexpected technical effect.

Description

A technetium 99 [Tc] methylene diphosphonate oral preparation and preparation method and application thereof Technical Field

[0001] The present invention relates to technetium [ 99 The technical field of oral preparations of methylene diphosphonates, particularly a technetium [ 99 [Tc] methylene diphosphonate oral preparation and its preparation method and application. Background Art

[0002] technetium[ 99 Tc] methylene diphosphonate is a 99 The chelate formed by Tc[1] after reduction with stannous chloride and methylene diphosphonate can inhibit the synthesis of prostaglandins and the release of histamine, and can produce anti-inflammatory and analgesic effects. It is mainly used to treat rheumatoid arthritis (RA), ankylosing spondylitis, femoral head necrosis, osteoarthritis, osteoporosis, psoriatic arthritis, bone metastases, multiple myeloma and other diseases. At present, technetium[ 99 Tc]methylene diphosphonic acid ( 99 The main published administration methods of Tc-MDP) salts include injection (preparations include injection preparations and lyophilized powder injections) and oral administration (preparations are ordinary coated tablets).

[0003] The advantage of injection is that the drug enters the blood circulation system directly, has high bioavailability and rapid onset of action. However, the production process of injections is strict and the cost is high. In addition, pain during injection, local induration of injection sites, and vascular inflammation caused by intravenous injection are all problems in the clinical application of injections. In addition, technetium [ 99 Tc] methylene diphosphonate injection requires intravenous drip, and patient compliance is poor.

[0004] Chinese patent CN114948890A discloses a preparation for oral administration - technetium [ 99 Tc] methylene diphosphonate coated tablets and their preparation method, the route of administration is oral, which has the advantage of avoiding injection administration and improving the patient's compliance to a certain extent. However, due to the 99 [Tc] The main ingredient of methylene diphosphonate tablets contains a large amount of methylene diphosphonate. Oral tablets of bisphosphonate compounds have obvious disadvantages such as gastrointestinal irritation and low bioavailability, resulting in poor patient compliance when taking the coated tablets. Patients can only take the medicine in the morning. In order to deliver the medicine to the stomach as quickly as possible and reduce irritation to the esophagus, the medicine should be taken with a full glass of water in the early morning, and lying down should be avoided for at least 30 minutes after taking the medicine and before the first meal of the day.

[0005] Therefore, a technetium[ 99[Tc] methylene diphosphonate oral preparations can improve bioavailability, reduce gastrointestinal irritation, and improve patient compliance, which is of great significance.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to: 99 Oral preparations of technetium [ 99 [Tc] methylene diphosphonate oral preparation and preparation method thereof. While ensuring efficacy, the oral preparation improves the formulation of the preparation raw materials and overcomes the temperature limitation of the previous process, thereby reducing the dosage, alleviating toxic and side effects such as gastrointestinal irritation, and improving the compliance and safety of drug use.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is:

[0009] A technetium 99 The methylene diphosphonate oral preparation is prepared by including the following raw materials in parts by weight:

[0010] Methylene diphosphonic acid: 5 to 200 parts;

[0011] Reducing agent: 2×10 -3 Servings ~ 20 servings;

[0012] Technetium [ 99 Sodium tc]ate: 5×10 -5 Servings~5000×10 -5 share;

[0013] 10 to 1000 parts of adhesive;

[0014] Solvent 10 parts~1×10 5 share;

[0015] Wherein, the high-technetium [ 99 Tc] sodium sulfate weight parts 99 Tc is calculated; the adhesive is made of high molecular polymer material;

[0016] Among them, the use of methylene diphosphonic acid, reducing agents and high-technetium [ 99 Technetium [ 99 Tc] methylene diphosphonate, and promptly 99 The invention discloses a method for preparing the invention by dissolving a methylene diphosphonate in a solvent, forming a mixed liquid with an adhesive, and spray drying the mixed liquid. The outlet temperature of the spray drying process does not exceed 115°C.

[0017] The present invention provides a technetium [ 99 The methylene diphosphonate oral preparation is prepared by including the following raw materials in parts by weight: methylene diphosphonic acid: 5 to 200 parts; reducing agent: 2×10 -3 ~20 parts; high technetium [ 99 Sodium tc]ate: 5×10 -5 Servings~5000×10 -5 parts; adhesive 10 parts to 1000 parts; solvent 10 parts to 1×10 5 Parts; wherein, the high technetium [ 99 Tc] sodium sulfate weight parts 99 Tc is calculated; the adhesive is made of polymer material; wherein, methylene diphosphonic acid, a reducing agent and high technetium [ 99 Technetium [ 99 Tc] methylene diphosphonate, and promptly 99 The invention discloses a method for preparing the technetium [ 99 Tc] methylene diphosphonate can be treated in time and the temperature of the spray drying air inlet can be controlled. 99 The change of the crystal form of methylene diphosphonate makes the permeability of human biological membrane better and the bioavailability is effectively improved. At the same time, the application adopts a high molecular polymer material, which, on the one hand, can make the oral preparation almost completely dissolve in the stomach, and on the other hand, can further improve the permeability of human biological membrane; in the high molecular polymer material and the timing and temperature control of spray drying, the technetium [ 99 The oral preparation of [Tc] methylene diphosphonate has good bioavailability. While achieving the same drug efficacy, it can reduce gastrointestinal irritation and improve patient compliance, achieving unexpected technical effects.

[0018] Furthermore, the reducing agent is at least one of stannous chloride, stannous fluoride, sodium bisulfite, sodium metabisulfite, gentisic acid and thiourea dioxide.

[0019] Furthermore, the air outlet temperature during the spray drying process is 65°C to 115°C.

[0020] Furthermore, the adhesive is at least one of a first adhesive and a second adhesive; the first adhesive is at least one of hydroxypropyl methylcellulose, polyethylene glycol polymer, povidone, and Soluplus, and the second adhesive is at least one of copovidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, trimethylaminoethyl methacrylate copolymer, hydroxypropyl cellulose, and polymethacrylate.

[0021] Furthermore, the solvent includes at least one of a first solvent and a second solvent; the first solvent is water, and the second solvent is at least one of methanol, ethanol, acetone, and tetrahydrofuran; wherein, when the adhesive used is the first adhesive or a mixed adhesive in which the weight ratio of the first adhesive to the second adhesive is 50:50 to 99:1, the solvent to be used is the first solvent or a mixed solvent in which the weight ratio of the first solvent to the second solvent is 30:70 to 99:1; when the adhesive used is the second adhesive or a mixed adhesive in which the weight ratio of the first adhesive to the second adhesive is 1:99 to 49:51, the solvent to be used is a mixed solvent in which the weight ratio of the first solvent to the second solvent is 5:95 to 70:30.

[0022] The above adaptation can improve the compatibility between the raw materials during the preparation process, making the drug permeability of the later preparation better.

[0023] Furthermore, it also includes 0.5 to 100 parts of an absorption enhancer, wherein the absorption enhancer includes at least one of a first absorption enhancer and a second absorption enhancer; the first absorption enhancer is at least one of sodium caprate, carboxymethyl chitosan, sodium caprylate, poloxamer-188, sodium laurate sulfate, sodium lauryl sulfate, caprylcarnitine, sodium deoxycholate, carbomer, chitosan, caprylic acid capric acid macrogol glyceride, and diethylenetriamine pentaacetic acid; the second absorption enhancer is at least one of vitamin E polyethylene glycol succinate, polyoxyethylene 40 hydrogenated castor oil, chitosan oligosaccharide, cell-penetrating peptide, propylene glycol monolaurate, and oleic acid macrogol glyceride; when the adhesive is used as the first adhesive or the weight ratio of the first adhesive to the second adhesive is 50:50 to 50:50, the absorption enhancer is preferably selected from the group consisting of sodium caprate, carboxymethyl chitosan, sodium caprylate, poloxamer-188, sodium laurate sulfate, sodium lauryl sulfate, caprylcarnitine, sodium deoxycholate, carbomer, chitosan, caprylic acid capric acid macrogol glyceride, and diethylenetriamine pentaacetic acid; and the second absorption enhancer is at least one of vitamin E polyethylene glycol succinate, polyoxyethylene 40 hydrogenated castor oil, chitosan oligosaccharide, cell-penetrating peptide, propylene glycol monolaurate, and oleic acid macrogol glyceride. When the weight ratio of the first absorption enhancer to the second absorption enhancer is 1:99:1, the absorption enhancer to be used is the first absorption enhancer or a mixed absorption enhancer with the weight ratio of the first absorption enhancer to the second absorption enhancer being 40:60 to 80:20, and the solvent to be used is the first solvent or a mixed solvent with the weight ratio of the first solvent to the second solvent being 30:70 to 99:1; when the adhesive to be used is the second adhesive or a mixed adhesive with the weight ratio of the first adhesive to the second adhesive being 1:99 to 49:51, the absorption enhancer to be used is the second absorption enhancer or a mixed absorption enhancer with the weight ratio of the first absorption enhancer to the second absorption enhancer being 1:99 to 60:40, and the solvent to be used is a mixed solvent with the weight ratio of the first solvent to the second solvent being 5:95 to 70:30.

[0024] The addition of an absorption enhancer can increase the drug's lipid solubility and further enhance the drug's permeability through biological membranes. Furthermore, the above configuration can be combined with an adhesive to enhance compatibility and increase solution stability.

[0025] Furthermore, it further comprises 5 to 500 parts of a diluent, or / and 10 to 100 parts of a disintegrant, or / and 5 to 50 parts of a lubricant.

[0026] Furthermore, the diluent is one or more of pregelatinized starch, microcrystalline cellulose and anhydrous lactose; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose; and the lubricant is one or more of stearic acid lubricants, talc, micro-powdered silica and silicon dioxide.

[0027] Another object of the present invention is to provide the above-mentioned technetium [ 99 A method for preparing an oral preparation of Tc]methylene diphosphonate.

[0028] A technetium [ 99 The preparation method of an oral preparation of a methylene diphosphonate is provided, wherein the oral preparation is a capsule or a tablet, comprising the following steps:

[0029] Step 1: Weigh a reducing agent, add hydrochloric acid solution to dissolve it, and obtain a first mixed material;

[0030] Step 2: mixing the first mixed material obtained in step 1 with an aqueous solution of methylene diphosphonic acid, and then adding sodium hydroxide solution to adjust the pH to 5-7 to obtain a second mixed material;

[0031] Step 3, the second mixed material obtained in step 2 is mixed with high technetium [ 99 Tc] sodium salt, dried, crushed, sieved, and obtained technetium [ 99 Tc]methylene diphosphonate;

[0032] Step 4: The technetium obtained in step 3 99 Tc] methylene diphosphonate is added to the solvent, stirred to dissolve, and the binder is added.

[0033] If there is an absorption enhancer, and / or a diluent, and / or a disintegrant, add them together and stir to mix evenly;

[0034] Step 5: spray-dry the prepared solution, collect the wet solid dispersion from the cyclone separator, dry-granulate it, add a lubricant if necessary, mix it, and then fill it into a capsule to obtain a capsule oral preparation; or press it into tablets to obtain oral tablets.

[0035] The present invention provides technetium [ 99 The invention relates to an oral preparation of methylene diphosphonate, which has a simple preparation process and is easy to promote and apply.

[0036] Another object of the present invention is to provide the above-mentioned technetium [ 99 Application of oral formulations of [Tc] methylene diphosphonate.

[0037] The above-mentioned technetium[ 99 Application of oral preparations of [Tc] methylene diphosphonate in the treatment of rheumatoid arthritis, ankylosing spondylitis, femoral head necrosis, osteoarthritis, osteoporosis, psoriatic arthritis, bone metastases, and multiple myeloma.

[0038] In summary, due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0039] 1. The present invention provides a technetium [ 99 The methylene diphosphonate oral preparation is prepared by including the following raw materials in parts by weight: methylene diphosphonic acid: 5 to 200 parts; reducing agent: 2×10 -3 ~20 parts; high technetium [ 99 Sodium tc]ate: 5×10 -5 Servings~5000×10 -5 parts; adhesive 10 parts to 1000 parts; solvent 10 parts to 1×105 Parts; wherein, the high technetium [ 99 Tc] sodium sulfate weight parts 99 Tc is calculated; the adhesive is made of polymer material; wherein, methylene diphosphonic acid, a reducing agent and high technetium [ 99 Technetium [ 99 Tc] methylene diphosphonate, and promptly 99 The invention discloses a method for preparing the technetium [ 99 Tc] methylene diphosphonate can be treated in time and the temperature of the spray drying air inlet can be controlled. 99 The change of the crystal form of methylene diphosphonate makes the permeability of human biological membrane better and the bioavailability is effectively improved. At the same time, the application adopts a high molecular polymer material, which, on the one hand, can make the oral preparation almost completely dissolve in the stomach, and on the other hand, can further improve the permeability of human biological membrane; in the high molecular polymer material and the timing and temperature control of spray drying, the technetium [ 99 The oral preparation of [Tc] methylene diphosphonate has good bioavailability. While achieving the same drug efficacy, it can reduce gastrointestinal irritation and improve patient compliance, achieving unexpected technical effects.

[0040] 2. The present invention provides technetium [ 99 The invention relates to an oral preparation of methylene diphosphonate, which has a simple preparation process and is easy to promote and apply.

[0041] 3. The present invention provides technetium [ 99 Application of oral preparations of [Tc] methylene diphosphonate in the treatment of rheumatoid arthritis, ankylosing spondylitis, femoral head necrosis, osteoarthritis, osteoporosis, psoriatic arthritis, bone metastases, and multiple myeloma. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] FIG1 is a drug concentration-time curve of Example 1 and Comparative Example 1.

[0043] Figure 2 is a sample diagram prepared in Comparative Example 3.

[0044] Figure 3 shows the different formulations of pH 6.8 medium in Experimental Example 1. 99 Dissolution curve of Tc.

[0045] FIG4 is the dissolution curve of MDP in different formulations in a pH 6.8 medium in Experimental Example 1.

[0046] FIG5 is a drug concentration-time curve in Experimental Example 2.

[0047] FIG6 shows the effects of the drugs in Experimental Example 3 on the proliferation of rat osteoblasts (x±s, n=6).

[0048] FIG. 7 shows the effects of the drugs in Experimental Example 3 on the proliferation of rat osteoclasts (x±s, n=6).

[0049] FIG8 shows the effects of the drugs in Experimental Example 5 on the serum PGE2 level in rats (x±s, n=8-10).

[0050] Figure 9 shows the effect of the drugs in Experimental Example 5 on the serum TNF-α level in rats ( n=8-10). DETAILED DESCRIPTION

[0051] The present invention will be described in detail below with reference to the accompanying drawings.

[0052] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0053] In the following examples and comparative examples, the specifications of some raw materials involved are shown in Table 1.

[0054] Table 1

[0055] Example 1:

[0056] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0057] Filler prescription:

[0058] Methylene diphosphonic acid: 50g;

[0059] Stannous chloride: 2g;

[0060] Technetium [ 99 Sodium tc]ate: 1×10 -3 g(with 99 Tc meter);

[0061] Copolyvidone VA64: 100g

[0062] 30% ethanol solution: 3000g;

[0063] Magnesium stearate: 1g;

[0064] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 [Tc] methylene diphosphonate is added to an ethanol aqueous solution and stirred to fully dissolve. Then, the prescribed amount of copovidone VA64 is added and mixed evenly. The mixed solution is spray-dried (air outlet temperature 115°C) to obtain a solid wet product, which is then vacuum-dried to obtain a dry solid. The material is dry-granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), with a crushing screen size of 1.0 mm, and the crushed dry particles are collected. The prescribed amount of magnesium stearate is added to the dry-granulated particles and continued to be manually mixed for 3 minutes. The particles are filled into the prepared hydropropyl methylcellulose capsules according to the target loading amount.

[0065] Comparative Example 1

[0066] Comparative Example 1 is different from Example 1 except that the type of adhesive is changed to a non-polymeric material, and other conditions remain unchanged.

[0067] Filler prescription:

[0068] Methylene diphosphonic acid: 50g;

[0069] Stannous chloride: 2g;

[0070] Technetium [ 99 Sodium tc]ate: 1×10 -3 g(with 99 Tc meter);

[0071] Starch: 100g

[0072] 30% ethanol solution: 3000g;

[0073] Magnesium stearate: 1g;

[0074] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99[Tc] methylene diphosphonate was added to an ethanol aqueous solution and stirred to fully dissolve, followed by adding the prescribed amount of starch and mixing. The mixed solution was spray-dried to obtain a solid wet product, and the dried solid was vacuum-dried. The material was dry-granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), with a crushing screen size of 1.0 mm, and the crushed dry granules were collected. The prescribed amount of magnesium stearate was added to the dry-granulated granules and continued to be manually mixed for 3 minutes. The granules were filled into the obtained hypromellose capsules according to the target loading.

[0075] 1 Experimental drug

[0076] 1.1 Test drug

[0077] The drugs of Example 1 and Comparative Example 1 were ground into extremely fine powders, dissolved in physiological saline, mixed evenly, and diluted to the desired concentration before use.

[0078] 1.2 Comparator drugs

[0079] technetium[ 99 Tc] methylene diphosphonate powder injection (same as Example 1 of Chinese Patent CN103203032B), mix well, and dilute to the required concentration before use.

[0080] 2 Experimental methods

[0081] 2.1 Dosage regimen and sample collection

[0082] 81 SD rats that had been fasted overnight were randomly divided into three groups and given 4.0×10 -4 mg / kg (in technetium) Example 1, 4.0×10 -4 mg / kg (in technetium) of comparative example 1 and tail vein injection of 4.0×10 -4 mg / kg (in technetium) technetium[ 99 Methylene diphosphonate powder injection. At 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 12 hours after each administration, three rats were selected from each group. Whole blood was extracted from the abdominal aorta by rapid dissection, and then anticoagulated and centrifuged to separate the plasma for processing.

[0083] 2.2 Sample processing

[0084] Whole blood was drawn from the abdominal aorta of rats and anticoagulated with sodium citrate before centrifugation to separate the plasma. 0.8 mL of plasma was taken and digested with 1.8 mL of 30% hydrochloric acid. After complete digestion, 0.65 mL was taken and diluted to 6.5 mL with 0.1% Triton 100 (prepared with purified water). After filtering with a 0.22 μm filter membrane, 5 mL was introduced into ICP-MS to determine the response value.

[0085] 2.3 Data Analysis

[0086] Pharmacokinetic analysis was performed using DAS 2.1.1 software. Absolute bioavailability was calculated using the following formula: F = AUC 口服 AUC 静脉 ×100%.

[0087] 3 Experimental results

[0088] The serial sampling times were plotted against rat plasma concentrations, and the results are shown in Figure 1. The main pharmacokinetic parameters for each group were calculated using DAS pharmacokinetic software, and the results are shown in Table 2. Compared with Comparative Example 1, the peak concentration (Cmax) of Example 1 increased from 0.0079±0.13 μg / mL to 0.0099±0.150 μg / mL; the area under the curve (AUC) increased from 0.041 μg / mL*h to 0.049 μg / mL*h; and the absolute bioavailability increased from 1.19% to 1.42%. This indicates that both the exposure and bioavailability of Example 1 in rats were slightly increased compared to Comparative Example 1.

[0089] Table 2 Main pharmacokinetic parameters in rats

[0090] Comparative Example 2

[0091] The raw materials of Comparative Example 2 were unchanged from those of Example 1, except that spray drying was not used, and the other parameters remained unchanged.

[0092] Filler prescription:

[0093] Methylene diphosphonic acid: 50g;

[0094] Stannous chloride: 2g;

[0095] Technetium [ 99 Sodium tc]ate: 1×10 -3 g(with 99 Tc meter);

[0096] Copolyvidone VA64: 100g

[0097] Magnesium stearate: 1g;

[0098] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 The solution was rotary evaporated at 50℃, dried at 105℃, crushed, and passed through an 80-mesh sieve to obtain technetium [ 99Tc] methylene diphosphonate, followed by the prescribed amount of copovidone VA64, and thorough mixing. The material was dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), using a 1.0 mm sieve size, and the resulting dry granules were collected. The prescribed amount of magnesium stearate was added to the dry granules and manual mixing continued for 3 minutes. The granules were then filled into the resulting hypromellose capsules according to the target loading.

[0099] The preparation samples were tested by HPLC. 99 Tc content, HPLC conditions: Waters Xterra RP C8 column (with C8 pre-column); 0.03 mol / L sodium acetate solution (pH adjusted to 5.00±0.05 with acetic acid) as the mobile phase (flow rate, 0.5 mL / min), detection wavelength, 254 nm, column temperature, 25°C, injection volume, 20 μL.

[0100] Each unit dose sample (if 10 sets of Yunke main components are used as 1 unit dose sample, i.e. MDP, SnCl2, 99 Add about 2 mL of water to the solution (Tc, and a small amount of NaCl to adjust the pH value). After complete dissolution, add 2 mL of H2O2 and evaporate to dryness in a water bath. Then, dry at 105°C for more than 2 hours to remove H2O2, and add 2 mL of water to dissolve. Filter through a 0.22 μm microporous membrane to collect the filtrate, and perform HPLC analysis. 99 Tc content.

[0101] The specific configuration method is as follows:

[0102] Background solution: Precisely weigh all ingredients except technetium (prepare for 50 unit doses), including MDP, SnCl₂, and NaOH (adjust the solution to neutrality), add a certain volume of water for injection until completely dissolved, concentrate to approximately 50 mL while the water is slightly boiling, cool to room temperature, add 100 mL of H₂O₂, mix thoroughly, and allow to stand for 10 minutes. Concentrate while slightly boiling until the solution is nearly powdery, then evaporate to dryness in a water bath. Dry at 105°C for at least 2 hours to remove the H₂O₂, dissolve in water, transfer to a 100 mL volumetric flask, and dilute to the mark for later use.

[0103] Standard working curve: Use a pipette to accurately measure a certain amount of high concentration 99 Add the Tc solution to a 10 mL volumetric flask, dilute to the mark with water for injection, and shake well to obtain a concentration of approximately 10 μg / mL. 99 Tc solution.

[0104] Use a pipette to precisely measure 9.4 mL of the standard background solution, take 6 portions, and place them in 10 mL volumetric flasks. Add 10 μg / mL TcO to the labeled beakers. 4-Solution, 0.05mL, 0.10mL, 0.15mL, 0.20mL, 0.25mL, 0.30mL, add water for injection to 10mL, and obtain 99 Tc series standard curve solutions (0.05 μg / mL, 0.10 μg / mL, 0.15 μg / mL, 0.20 μg / mL, 0.25 μg / mL, 0.30 μg / mL) for HPLC detection.

[0105] Example 1 and Comparative Example 2 99 The HPLC test data of Tc content is shown in Table 3. As shown in Table 3, the technetium content of Example 1 is 98.3%, which is significantly higher than that of Comparative Example 2, which is 48.5%, indicating that 99 Tc complex solutions are unstable under high temperature conditions for a long time and need to be quickly converted from solution to solid state.

[0106] Table 3 Preparation 99 Tc content test results

[0107] Comparative Example 3

[0108] Comparative Example 3: The raw materials of Example 1 remain unchanged, and the outlet temperature of the spray dryer is changed to 55°C, while other parameters remain unchanged.

[0109] Filler prescription:

[0110] Methylene diphosphonic acid: 50g;

[0111] Stannous chloride: 2g;

[0112] Technetium [ 99 Sodium tc]ate: 1×10 -3 g(with 99 Tc meter);

[0113] Copolyvidone VA64: 100g

[0114] 30% ethanol solution: 3000g;

[0115] Magnesium stearate: 1g;

[0116] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99[Tc] methylene diphosphonate is added to an ethanol aqueous solution and stirred to fully dissolve, and then the prescribed amount of copovidone VA64 is added and mixed evenly. The mixed solution is spray-dried to obtain a solid wet product, and the dry solid is obtained by vacuum drying, with an outlet temperature of 55°C. The material is dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), the crushing screen size is 1.0mm, and the crushed dry particles are collected. The prescribed amount of magnesium stearate is added to the dry granulated particles and continued to be manually mixed for 3 minutes. The particles are filled into the prepared hydropropyl methylcellulose capsules according to the target loading amount.

[0117] When the outlet temperature was around 55°C, the resulting sample was a hard lump (as shown in Figure 2). Considering that purified water was used as the solvent, the water was not fully evaporated at lower outlet temperatures, resulting in a large amount of powder on the inner walls of the drying tower and cyclone separator. This resulted in a relatively low final yield of the complex, only 45%, and a high moisture content of around 12%. Therefore, after adjusting the outlet temperature to around 75°C, the resulting complex had a loose texture, meeting the experimental requirements. To further reduce the moisture content in the complex, the outlet temperature was controlled at 80°C and 85°C, which controlled the moisture content of the final product to around 8%, increasing the final yield to 57%.

[0118] Example 2:

[0119] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0120] Filler prescription:

[0121] Methylene diphosphonic acid: 50g;

[0122] Stannous chloride: 2g;

[0123] Technetium [ 99 Sodium tc]ate: 1×10 -3 g(with 99 Tc meter);

[0124] Copolyvidone VA64: 100g

[0125] 30% ethanol solution: 3000g;

[0126] Magnesium stearate: 1g;

[0127] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99[Tc] methylene diphosphonate is added to an ethanol aqueous solution and stirred to fully dissolve, followed by the addition of the prescribed amount of copovidone VA64 and mixing. The mixed solution is spray-dried (air outlet temperature 80°C) to obtain a solid wet product, which is then vacuum-dried to obtain a dry solid. The material is dry-granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), with a crushing screen size of 1.0 mm, and the crushed dry particles are collected. The prescribed amount of magnesium stearate is added to the dry-granulated particles and continued to be manually mixed for 3 minutes. The particles are filled into the prepared hydropropyl methylcellulose capsules according to the target loading amount.

[0128] Example 3

[0129] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0130] Filler prescription:

[0131] Methylene diphosphonic acid: 50g;

[0132] Stannous chloride: 2g;

[0133] Technetium [ 99 Sodium tc]ate: 1×10 -3 g(with 99 Tc meter);

[0134] Povidone K30: 100g

[0135] Sodium caprate: 20g

[0136] 30% ethanol solution: 3000g;

[0137] Magnesium stearate: 1g;

[0138] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 [Tc] methylene diphosphonate is added to an ethanol aqueous solution and stirred to fully dissolve. Then, the prescribed amount of povidone K30 and sodium decanoate are added and mixed evenly. The mixed solution is spray-dried (air outlet temperature 90°C) to obtain a solid wet product, which is then vacuum-dried to obtain a dry solid. The material is dry-granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), with a crushing screen size of 1.0 mm, and the crushed dry particles are collected. The prescribed amount of magnesium stearate is added to the dry-granulated particles and continued to be manually mixed for 3 minutes. The particles are filled into the prepared hydropropyl methylcellulose capsules according to the target loading amount.

[0139] Example 4

[0140] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0141] Filler prescription:

[0142] Methylene diphosphonic acid: 5g;

[0143] Stannous chloride: 2×10 -3 g;

[0144] Sodium bisulfite: 0.1g;

[0145] Technetium [ 99 Sodium tc]ate: 5×10 -5 g(with 99 Tc meter);

[0146] Macrogol 2000: 2g

[0147] Hydroxypropyl methylcellulose acetate succinate: 160g

[0148] Sodium caprate: 1g

[0149] Propylene glycol monolaurate: 1g

[0150] Magnesium stearate: 3g

[0151] Water-acetone-tetrahydrofuran solution (2:3:5): 2000g

[0152] Preparation method: Weigh the prescribed amount of stannous chloride and sodium bisulfite, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 [Tc] methylene diphosphonate is added to an ethanol-water solution and stirred until fully dissolved. The prescribed amount of polyethylene glycol 2000 and sodium caprate are then added and mixed thoroughly to fully dissolve. The mixed solution is spray-dried (air outlet temperature 75°C) and vacuum-dried to obtain a solid. This material is thoroughly mixed with the prescribed amount of hydroxypropyl methylcellulose acetate succinate and propylene glycol monolaurate for 3 minutes. Dry granulation is performed according to appropriate process parameters (hydraulic pressure, feed speed, roller speed) using a 1.0 mm sieve size. The pulverized dry granules are collected. The prescribed amount of magnesium stearate is added to the dry-granulated granules and manual mixing is continued for 3 minutes. The granules are then filled into the prepared empty hydroxypropyl methylcellulose capsules according to the target loading amount.

[0153] Example 5

[0154] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0155] Filler prescription:

[0156] Methylene diphosphonic acid: 200g;

[0157] Gentisic acid: 1g;

[0158] Technetium [ 99 Sodium tc] acid: 0.05g (in 99 Tc meter);

[0159] Soluplus: 25g

[0160] Carbomer: 3g

[0161] Magnesium stearate: 1g

[0162] 25% acetone solution: 3000g

[0163] Preparation method: Weigh the prescribed amount of gentisic acid, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 [Tc] methylene diphosphonate is added to an ethanol-water solution and stirred until fully dissolved. The prescribed amount of Soluplus and carbomer are then added and mixed until fully dissolved. The mixed solution is spray-dried (air outlet temperature 100°C) and vacuum-dried to obtain a solid. The material is dry-granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed) using a 1.0mm sieve size, and the pulverized dry granules are collected. The prescribed amount of magnesium stearate is added to the dry-granulated granules and manual mixing is continued for 3 minutes. The granules are then filled into the prepared hydropropyl methylcellulose capsules according to the target loading.

[0164] Example 6

[0165] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0166] Filler prescription:

[0167] Methylene diphosphonic acid: 100g;

[0168] Stannous chloride: 5g;

[0169] Technetium [ 99 Sodium tc]ate: 2×10 -3 g(with99 Tc meter);

[0170] Hydroxypropyl methylcellulose acetate succinate: 25g

[0171] Polymethacrylate: 5g

[0172] Chitosan oligosaccharide: 20g

[0173] Oleic acid macrogol glycerides: 10g

[0174] Silicon dioxide: 1g

[0175] 50% tetrahydrofuran solution: 4000g

[0176] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 [Tc] methylene diphosphonate is added to a tetrahydrofuran aqueous solution and stirred to fully dissolve. Then, the prescribed amount of chitosan oligosaccharide and polymethacrylate are added and mixed evenly to fully dissolve. The mixed solution is spray-dried (air outlet temperature 95°C) and vacuum-dried to obtain a solid. This material is fully mixed with the prescribed amount of hydroxypropyl methylcellulose acetate succinate, oleic acid macrogol glyceride, and silicon dioxide for 3 minutes. Dry granulation is performed according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), and the grinding screen size is 1.0 mm. The crushed dry particles are collected. The prescribed amount of magnesium stearate is added to the dry granulated particles and continued to be manually mixed for 3 minutes. The particles are filled into the prepared hydropropyl methylcellulose capsules according to the target loading amount.

[0177] Example 7: Technetium of the present invention [ 99 [Tc] Methylene diphosphonate solid dispersion tablets (1000 tablets)

[0178] Methylene diphosphonic acid: 100g;

[0179] Stannous chloride: 0.25g;

[0180] Technetium [ 99 Sodium tc]ate: 2.5×10 -4 g(with 99 Tc meter);

[0181] Copolyvinylpyrrolidone-VA64: 15g

[0182] Sodium lauryl sulfate: 15g

[0183] 35% acetone solution: 3000g

[0184] Microcrystalline cellulose: 100g;

[0185] Magnesium stearate: 2g;

[0186] Micro powder silica gel: 1g;

[0187] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 Tc] methylene diphosphonate was added to the prescribed amount of 35% acetol solution, stirred to fully dissolve, and then the prescribed amount of copolypyrrolidone-VA64 and sodium lauryl sulfate were added and mixed evenly to fully dissolve. The mixed solution was spray dried (air outlet temperature 80 ° C) and vacuum dried to obtain a solid. 99 The solid dispersion of methylene diphosphonate and the prescribed amount of microcrystalline cellulose were placed in a suitable PE bag, manually mixed for 3 minutes, and then passed through a 40-mesh sieve. The sieved material was further placed in a suitable PE bag and manually mixed for 20 minutes. The mixed material was dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, and roller speed). The crushing screen size was 1.0 mm. The crushed dry granules were collected, and the prescribed amount of magnesium stearate and micropowdered silica were added to the dry-granulated granules and continued to be manually mixed for 3 minutes. The tablets were directly compressed to obtain the tablets.

[0188] Example 8: Technetium of the present invention [ 99 [Tc] Methylene diphosphonate solid dispersion tablets (1000 tablets)

[0189] Methylene diphosphonic acid: 5g;

[0190] Stannous chloride: 2×10 -3 g;

[0191] Sodium bisulfite: 0.1g;

[0192] Technetium [ 99 Sodium tc]ate: 5×10 -5 g(with 99 Tc meter);

[0193] Hydroxypropyl cellulose: 100g

[0194] 60% methanol solution: 3000g

[0195] Caprylic / capric macrogol glycerides: 25g

[0196] Microcrystalline cellulose: 10g;

[0197] Sodium carboxymethyl starch: 10g;

[0198] Magnesium stearate: 0.5g;

[0199] Talc: 1g;

[0200] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 Tc] methylene diphosphonate was added to a 60% methanol solution, stirred to dissolve it completely, and then the prescribed amount of hydroxypropyl cellulose was added and mixed evenly to dissolve it completely. The mixed solution was spray dried (air outlet temperature 90°C) and vacuum dried to obtain a solid. 99 The solid dispersion of methylene diphosphonate, microcrystalline cellulose, caprylic / capric macrogol glycerides, and sodium carboxymethyl starch are placed in a suitable PE bag in sequence and manually mixed for 3 minutes. The mixture is then passed through a 40-mesh sieve. The sieved material is further placed in a suitable PE bag and manually mixed for 20 minutes. The mixed material is granulated according to appropriate process parameters (hydraulic pressure, feed speed, and roller speed). The crushing screen size is 1.0 mm. The crushed particles are collected, and the prescribed amount of magnesium stearate and talc are added to the granulated particles. The mixture is manually mixed for 3 minutes and then directly compressed into tablets.

[0201] Example 9: Technetium of the present invention [ 99 [Tc] Methylene diphosphonate solid dispersion tablets (1000 tablets)

[0202] Methylene diphosphonic acid: 200g;

[0203] Stannous chloride: 1g;

[0204] Technetium [ 99 Sodium tc]ate: 1×10 -3 g(with 99 Tc meter);

[0205] Trimethylaminoethyl methacrylate copolymer: 10g

[0206] Hydroxypropyl cellulose: 20g

[0207] Sodium deoxycholate: 2g

[0208] Vitamin E polyethylene glycol succinate: 1g

[0209] 55% tetrahydrofuran solution: 2500g

[0210] Anhydrous lactose: 20g;

[0211] Magnesium stearate: 2g;

[0212] Preparation method: Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 Tc] methylene diphosphonate was added to a 55% tetrahydrofuran solution and stirred to dissolve it completely. Then, trimethylaminoethyl methacrylate copolymer, hydroxypropyl cellulose, sodium deoxycholate and vitamin E polyethylene glycol succinate were added to the prescribed amount and mixed evenly to dissolve it completely. The mixed solution was spray dried (outlet temperature 85°C) and vacuum dried to obtain a solid. 99 The solid dispersion of methylene diphosphonate and the prescribed amount of anhydrous lactose were placed in a suitable PE bag in sequence and manually mixed for 3 minutes, and then passed through a 40-mesh sieve. The sieved material was further placed in a suitable PE bag and manually mixed for 20 minutes. The mixed material was dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, and roller speed). The crushing screen size was 1.0 mm. The crushed dry granules were collected, and the prescribed amount of magnesium stearate was added to the dry granules and continued to be manually mixed for 3 minutes. The tablets were directly compressed to obtain the tablets.

[0213] Example 10: Technetium of the present invention [ 99 [Tc] Methylene diphosphonate solid dispersion tablets (1000 tablets)

[0214] Methylene diphosphonic acid: 50g;

[0215] Stannous chloride: 0.25g;

[0216] Ascorbic acid: 0.25g;

[0217] Technetium [ 99 Sodium tc]ate: 2.5×10 -4 g(with 99 Tc meter);

[0218] Hydroxypropyl cellulose: 80g

[0219] Hydroxypropyl methylcellulose phthalate: 20g

[0220] Vitamin E polyethylene glycol succinate: 2g

[0221] Propylene glycol monolaurate: 4g

[0222] 45% acetone solution: 2000g

[0223] Pregelatinized starch: 150g;

[0224] Sodium carboxypropyl starch: 8g;

[0225] Magnesium stearate: 1g;

[0226] Silicon dioxide: 0.1g;

[0227] Preparation method: Weigh the prescribed amount of stannous chloride and ascorbic acid, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution is dried, crushed, and passed through an 80-mesh sieve, technetium [ 99 Tc] methylene diphosphonate was added to a 45% acetone solution, stirred to fully dissolve, and then the prescribed amount of hydroxypropyl cellulose and vitamin E polyethylene glycol succinate were added and mixed evenly to fully dissolve. The mixed solution was spray dried (air outlet temperature 100 ° C) and vacuum dried to obtain a solid. 99 The solid dispersion of methylene diphosphonate and the prescribed amount of pregelatinized starch, sodium carboxypropyl starch, magnesium stearate and silicon dioxide were placed in a suitable PE bag in sequence and manually mixed for 3 minutes, and then passed through a 40-mesh sieve. The sieved material was further placed in a suitable PE bag and manually mixed for 20 minutes. The mixed material was dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), and the crushing screen size was 1.0 mm. The crushed dry granules were collected, and the prescribed amount of magnesium stearate and silicon dioxide were added to the dry granulated granules and continued to be manually mixed for 3 minutes. The tablets were directly compressed to obtain the tablets.

[0228] Test Example 1:

[0229] The purpose of this experiment is to investigate the 99 Tc] methylene diphosphonate solid dispersion capsules and solid dispersion tablets and prior art technetium [ 99 Tc] methylene diphosphonate coated tablets and ordinary technetium [ 99 Comparison of the dissolution rates of Tc]methylene diphosphonate capsules.

[0230] 1 Experimental drug

[0231] 1.1 Test drug

[0232] technetium[ 99 Tc] Methylene diphosphonate dispersion capsules (same as Example 2)

[0233] technetium[ 99 Tc] methylene diphosphonate solid dispersion tablets (same as Example 8).

[0234] 1.2 Comparator drugs

[0235] Ordinary technetium[ 99 Methylene diphosphonate capsules: Each tablet contains 50 mg of methylene diphosphonate, 2 mg of stannous chloride, and 2 mg of pertechnetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc), anhydrous lactose 185mg, hydroxypropyl cellulose 8mg; colloidal silicon dioxide 2mg; disodium edetate 2mg; magnesium stearate 1mg. Preparation method: ① Weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution was dried, it was crushed and passed through an 80-mesh sieve to obtain 99 Tc-MDP complex powder. ② Premix and sieve: weigh the prescribed amount 99 The dried Tc-MDP complex powder (passed through a 40-100 mesh sieve and then weighed) and hydroxypropyl cellulose, colloidal silicon dioxide, and edetate disodium (passed through a 40-100 mesh sieve and then weighed) are sequentially placed in a suitable PE bag, mixed, and then passed through a 40-100 mesh sieve; ③ Mixing: The sieved materials are further placed in a suitable PE bag for mixing; ④ Dry Granulation: The mixed materials are dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), with a grinding screen size of 1.0 mm, and the pulverized dry granules are collected; ⑤ Total Blending: Magnesium stearate lubricant is added to the dry granulated granules and continued to mix; ⑥ Capsule Filling: The capsules are manually filled according to the target filling amount and locked.

[0236] technetium[ 99 Tc] methylene diphosphonate coated tablets, each tablet contains methylene diphosphonic acid 50 mg; stannous chloride 200 μg, high technetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc); octanoylcarnitine 40mg; microcrystalline cellulose 20mg; sodium carboxymethylcellulose 10mg, silicon dioxide 5mg, magnesium stearate 1mg. Each tablet contains methylcellulose 5mg, polyethylene glycol 400 1mg, iron oxide 1mg, titanium dioxide 1mg, and purified water: 50mg. Preparation method: Weigh the prescribed amount of stannous chloride, add an appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 The solution is dried, crushed, and passed through an 80-mesh sieve. The mixture is then mixed with octanoylcarnitine, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, and magnesium stearate, and then tableted and coated to obtain the product.

[0237] technetium[ 99Tc] methylene diphosphonate powder injection (same as Example 2 of Chinese Patent CN103203032B), mix well, and dilute to the required concentration before use.

[0238] 2 Experimental methods

[0239] 2.1 Dissolution testing

[0240] Solution Preparation: pH 6.8 Phosphonate Buffer: Dissolve 61g of potassium dihydrogen phosphonate and 8g of sodium hydroxide in 9L of purified water until the pH reaches 6.8. Degas the solution in a solvent preparation machine. Diluent: pH 6.8 Phosphonate Buffer.

[0241] Dissolution test method: The paddle method (with sinker) was used to determine the dissolution data of the capsules under the conditions of 500 mL, pH 6.8, and 50 rpm. The sampling points were: 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 75 min, 90 min, and 120 min (maximum speed 250 rpm, 15 min).

[0242] 2.2 99 Tc detection:

[0243] Linear solution: 99 Tc standard solution (10 mg / L): Pipette 0.9 ml of Na 99 Add TcO4 solution to a 10ml volumetric flask, add purified water to dilute to the mark, and shake well.

[0244] Stock solution: Pipette 0.1 ml of Tc standard solution (10 mg / L), dilute to 10 ml with diluent, and shake well.

[0245] Pipette the stock solution according to Table 4, dilute to 10 ml with diluent, and shake well.

[0246] Table 4

[0247] Preparation of test solution: Take one sample capsule and sample at various time points according to the dissolution and release method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method 2) under the above dissolution conditions. Inject the sample into the ICP-MS according to the "ICP-MS Method".

[0248] 2.3 MDP Detection

[0249] UPLC chromatographic conditions

[0250] MS File

[0251] MS Tune File

[0252] Solution preparation:

[0253] Preparation of mobile phase A (5 mmol / L ammonium formate solution): Weigh 0.316 g of ammonium formate and dissolve it in 1 L of ultrapure water. Mix well, filter through a water-based microporous filter membrane, and sonicate.

[0254] Preparation of mobile phase B: Measure 2 L of methanol and filter it through a microporous filter membrane, then ultrasonicate.

[0255] 3 Experimental results

[0256] The test results are shown in Figures 3 and 4.

[0257] 3.1 99 Tc calibration curve linear results:

[0258] Table 5 pH 6.8 medium 99 Tc dissolution results

[0259] 3.2 MDP Detection

[0260] The in vitro dissolution results of MDP are shown in Table 6 below

[0261] Table 6 Dissolution results of MDP in pH 6.8 medium

[0262] Test Example 2:

[0263] This experimental example is a test of the technetium [ 99 Tc] methylene diphosphonate solid dispersion capsules, technetium [ 99 Tc] methylene diphosphonate solid dispersion tablets and prior art technetium [ 99 Tc] methylene diphosphonate coated tablets and ordinary technetium [ 99 Comparison of the bioavailability of Tc]methylene diphosphonate capsules.

[0264] 1 Experimental drug

[0265] 1.1 Test drug

[0266] technetium[ 99 [Tc] Methylene diphosphonate dispersion capsules (same as in Example 3) are ground into very fine powder and dissolved in physiological saline before use. The powder is mixed evenly and diluted to the desired concentration before use.

[0267] technetium[ 99 [Tc] Methylene diphosphonate solid dispersion tablets (same as Example 7) are ground into very fine powder and dissolved in physiological saline before use. The powder is mixed evenly and diluted to the desired concentration before use.

[0268] 1.2 Comparator drugs

[0269] Ordinary technetium[ 99 Tc] methylene diphosphonate capsules, each tablet contains methylene diphosphonate 50 mg, stannous chloride 2 mg, pertechnetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc), anhydrous lactose 185mg, hydroxypropyl cellulose 8mg; colloidal silicon dioxide 2mg; disodium edetate 2mg; magnesium stearate 1mg; Preparation method: ① weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution was dried, it was crushed and passed through an 80-mesh sieve to obtain 99 Tc-MDP complex powder. ② Premix and sieve: weigh the prescribed amount 99 The dried Tc-MDP complex powder (passed through a 40-100 mesh sieve and then weighed) was then placed in a suitable PE bag, mixed, and passed through a 40-100 mesh sieve. (3) Mixing: The sieved materials were further placed in a suitable PE bag for mixing. (4) Dry granulation: The mixed materials were dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), using a 1.0 mm sieve mesh size. The pulverized dry granules were collected. (5) Final blending: Magnesium stearate lubricant was added to the dry granules and continued mixing. (6) Capsule filling: The capsules were manually filled according to the target filling amount and sealed. Normal saline was added for uniform mixing before use. The capsules were diluted to the desired concentration immediately before use.

[0270] technetium[ 99 Tc] methylene diphosphonate coated tablets, each tablet contains methylene diphosphonic acid 50 mg; stannous chloride 200 μg, high technetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc); octanoylcarnitine 40mg; microcrystalline cellulose 20mg; sodium carboxymethylcellulose 10mg, silicon dioxide 5mg, magnesium stearate 1mg. Each tablet contains methylcellulose 5mg, polyethylene glycol 400 1mg, iron oxide 1mg, titanium dioxide 1mg, and purified water: 50mg. Preparation method: Weigh the prescribed amount of stannous chloride, add an appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 [Tc] sodium phosphate solution, mix evenly. After drying, crush the solution and pass it through an 80-mesh sieve. Then, mix it with octanoylcarnitine, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, and magnesium stearate, press it into tablets, and coat it. When using, add physiological saline, mix evenly, and dilute to the desired concentration before use.

[0271] technetium[ 99 Tc] methylene diphosphonate powder injection (same as Example 2 of Chinese Patent CN103203032B), mix well, and dilute to the required concentration before use.

[0272] 2 Experimental methods

[0273] 2.1 Dosage regimen and sample collection

[0274] 135 SD rats that had been fasted overnight were randomly divided into five groups and given 4.0×10 -4 mg / kg (in technetium) Technetium[ 99 Tc] methylene diphosphonate dispersion capsules, 4.0×10 -4 mg / kg (in technetium) technetium[ 99 Tc] methylene diphosphonate dispersion tablets, 4.0×10 -4 mg / kg (in technetium) technetium[ 99 Tc] methylene diphosphonate capsules, 4.0×10 -4 mg / kg (in technetium) technetium[ 99 Tc] methylene diphosphonate coated tablets and tail vein injection of 4.0 × 10 -4 mg / kg (in technetium) technetium[ 99 Methylene diphosphonate powder injection. At 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 12 hours after each administration, three rats were selected from each group. Whole blood was extracted from the abdominal aorta by rapid dissection, and then anticoagulated and centrifuged to separate the plasma for processing.

[0275] 2.2 Sample processing

[0276] Whole blood was drawn from the abdominal aorta of rats and anticoagulated with sodium citrate before centrifugation to separate the plasma. 0.8 mL of plasma was taken and digested with 1.8 mL of 30% hydrochloric acid. After complete digestion, 0.65 mL was taken and diluted to 6.5 mL with 0.1% Triton 100 (prepared with purified water). After filtering with a 0.22 μm filter membrane, 5 mL was introduced into ICP-MS to determine the response value.

[0277] 2.3 Data Analysis

[0278] Pharmacokinetic analysis was performed using DAS 2.1.1 software. Absolute bioavailability was calculated using the following formula: F = AUC 胶囊 / 片剂 AUC 粉针剂 ×100%.

[0279] 3 Experimental results

[0280] The drug-time curves of the serial sampling times and the rat plasma concentrations were plotted, and the results are shown in Figure 5. The main pharmacokinetic parameters of each group were calculated using DAS pharmacokinetic software, and the results are shown in Table 7. 99 Tc] methylene diphosphonate capsules, technetium [ 99 Compared with Tc] methylene diphosphonate capsule-coated tablets, technetium [ 99 The half-life of [Tc] methylene diphosphonate dispersion capsules and dispersion tablets was extended from 2.97h and 2.72h to 7.51h and 7.83h; the time to peak concentration was extended from 0.5h to 1.0h; the peak concentration Cmax was reduced from 0.0196±0.158μg / mL and 0.0190±0.174μg / mL to 0.0134±0.161μg / mL and 0.0127±0.147μg / mL; the area under the concentration-time curve (AUC) was reduced from 0.1061μg / mL*h and 0.1052μg / mL*h to 0.0972μg / mL*h and 0.0925μg / mL*h; and the absolute bioavailability was reduced from 3.08% and 3.06% to 2.83% and 2.69%.

[0281] It can be seen that compared with the existing technology [ 99 Compared with Tc] methylene diphosphonate capsules and coated tablets, technetium [ 99 The exposure and bioavailability of the Tc] methylene diphosphonate dispersion capsules and dispersion tablets in rats were slightly reduced, but the peak time was delayed, and the blood concentration was stable in a high range at 0.5-2h. In addition, in terms of half-life, peak time, peak concentration and bioavailability, technetium [ 99 Tc] methylene diphosphonate dispersion capsules are similar to dispersion tablets. Therefore, the technetium [ 99 Tc] methylene diphosphonate dispersion capsules are superior to the existing technology [ 99 Tc] methylene diphosphonate capsules and coated tablets have a certain controlled-release effect.

[0282] Table 7 Main pharmacokinetic parameters in rats

[0283] Test Example 3:

[0284] This experimental example is a test of the technetium [ 99 Tc] methylene diphosphonate solid dispersion capsules, technetium [ 99 Tc] methylene diphosphonate solid dispersion tablets and prior art technetium [ 99 Tc] methylene diphosphonate coated tablets and ordinary technetium [ 99 Comparison of the efficacy of Tc]methylene diphosphonate capsules (effects on osteoblasts and osteoclasts in vitro).

[0285] 1 Experimental drug

[0286] 1.1 Test drug

[0287] technetium[ 99 [Tc] Methylene diphosphonate dispersion capsules (same as in Example 4) are ground into very fine powder and dissolved in physiological saline before use. The powder is mixed evenly and diluted to the desired concentration before use.

[0288] technetium[ 99 [Tc] Methylene diphosphonate solid dispersion tablets (same as in Example 8) are ground into very fine powder and dissolved in physiological saline before use. The powder is mixed evenly and diluted to the desired concentration before use.

[0289] 1.2 Comparator drugs

[0290] Ordinary technetium[ 99 Tc] methylene diphosphonate capsules, each tablet contains methylene diphosphonate 50 mg, stannous chloride 2 mg, pertechnetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc), anhydrous lactose 185mg, hydroxypropyl cellulose 8mg; colloidal silicon dioxide 2mg; disodium edetate 2mg; magnesium stearate 1mg; Preparation method: ① weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution was dried, it was crushed and passed through an 80-mesh sieve to obtain 99 Tc-MDP complex powder. ② Premix and sieve: weigh the prescribed amount 99 The dried Tc-MDP complex powder (passed through a 40-100 mesh sieve and then weighed) was then placed in a suitable PE bag, mixed, and passed through a 40-100 mesh sieve. (3) Mixing: The sieved materials were further placed in a suitable PE bag for mixing. (4) Dry granulation: The mixed materials were dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), using a 1.0 mm sieve mesh size. The pulverized dry granules were collected. (5) Final blending: Magnesium stearate lubricant was added to the dry granules and continued mixing. (6) Capsule filling: The capsules were manually filled according to the target filling amount and sealed. Normal saline was added for uniform mixing before use. The capsules were diluted to the desired concentration immediately before use.

[0291] technetium[ 99 Tc] methylene diphosphonate coated tablets, each tablet contains methylene diphosphonic acid 50 mg; stannous chloride 200 μg, high technetium [ 99 Tc] sodium chloride 1 μg (as 99Tc); octanoylcarnitine 40mg; microcrystalline cellulose 20mg; sodium carboxymethylcellulose 10mg, silicon dioxide 5mg, magnesium stearate 1mg. Each tablet contains methylcellulose 5mg, polyethylene glycol 400 1mg, iron oxide 1mg, titanium dioxide 1mg, and purified water: 50mg. Preparation method: Weigh the prescribed amount of stannous chloride, add an appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 [Tc] sodium phosphate solution and mix well. After drying, crush the solution and pass it through an 80-mesh sieve. Then, mix it with octanoylcarnitine, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, and magnesium stearate, press it into tablets, and coat it to obtain the product. When using, add physiological saline, mix well, and dilute to the desired concentration before use.

[0292] 1.3 Experimental cells

[0293] 1.3.1 Isolation and culture of osteoblasts

[0294] Calvarias were obtained from newborn SD rats and mice under sterile conditions. Connective tissue and periosteum were removed, and the bone fragments were minced and enzymatically digested. After discarding the digestion solution, the cells were resuspended in DMEM high-glucose medium supplemented with 10% fetal bovine serum and transferred to a culture dish. The cells were cultured in a 37°C, 5% CO2 incubator. Identification results showed that alkaline phosphatase and calcified nodules were positive. Cells were cultured in osteogenic induction medium starting at P2, and cells from P3 to P5 were used in subsequent experiments.

[0295] 1.3.2 Isolation and culture of osteoclasts

[0296] Long bones from the limbs of SD rats were obtained under sterile conditions. Soft tissue and epiphyses were removed from the bones. The bone marrow cavity and inner surface of the bones were repeatedly rinsed with α-MEM complete medium. The resulting bone marrow suspension was filtered through a 200-mesh cell sieve. The filtered cell suspension was evenly inoculated into culture flasks and cultured in a 37°C, 5% CO2 incubator. Cells were induced with M-CSF and RANKL. RACP staining was positive.

[0297] 2 Experimental methods

[0298] 2.1 MTT assay for osteoblast proliferation

[0299] Osteoblasts in logarithmic growth phase were cultured at a rate of 2×10 4 / mL were inoculated into 96-well cell culture plates, 100 μL per well, and cultured in a 37°C, 5% CO2 incubator for 24 h. The cells were then divided into four groups, each of which was replaced with blank culture medium, culture medium containing 2×10 -10 mol / L (in 99 Tc meter) technetium[ 99Tc] methylene diphosphonate dispersion capsules, 2×10 -10 mol / L (in 99 Tc meter) technetium[ 99 Tc] methylene diphosphonate dispersion tablets, 2×10 -10 mol / L (in 99 Tc meter) technetium[ 99 Tc] methylene diphosphonate capsules, 2×10 -10 mol / L (in 99 Tc meter) technetium[ 99 Tc] methylene diphosphonate-coated tablets were cultured in duplicate in six wells per group. After 24 hours of incubation, 40 μL of MTT (5 g / L) was added to each well before cell culture was terminated and incubated for another 4 hours. The supernatant was discarded and 150 μL of DMSO was added to each well. The cells were shaken for 10 minutes, and the absorbance (OD) of each well was measured at 490 nm.

[0300] 2.2 MTT assay for osteoclast proliferation

[0301] Osteoclasts in the logarithmic growth phase were cultured at a rate of 2×10 4 / mL were inoculated into 96-well cell culture plates, 100 μL per well, and cultured in a 37°C, 5% CO2 incubator for 24 h. The cells were then divided into four groups, each of which was replaced with blank culture medium, culture medium containing 2×10 -10 mol / L (in 99 Tc meter) technetium[ 99 Tc] methylene diphosphonate dispersion capsules, 2×10 -10 mol / L (in 99 Tc meter) technetium[ 99 Tc] methylene diphosphonate capsules, 2×10 -10 mol / L (in 99 Tc meter) technetium[ 99 Tc] methylene diphosphonate-coated tablets were cultured in duplicate in six wells per group. After 24 hours of incubation, 40 μL of MTT (5 g / L) was added to each well before cell culture was terminated and incubated for another 4 hours. The supernatant was discarded and 150 μL of DMSO was added to each well. The cells were shaken for 10 minutes, and the absorbance (OD) of each well was measured at 490 nm.

[0302] 3 Experimental results

[0303] 3.1 Drugs promote osteoblast proliferation

[0304] As shown in Figure 6, compared with the blank group, 2×10 -10 mol / L technetium[ 99 Tc] methylene diphosphonate dispersion capsules, 2×10 -10mol / L technetium[ 99 Tc] methylene diphosphonate dispersion tablets, 2×10 -10 mol / L technetium[ 99 Tc] methylene diphosphonate capsules, 2×10 -10 mol / L technetium[ 99 Tc] methylene diphosphonate coated tablets have a promoting effect on the proliferation of osteoblasts, and the difference is statistically significant (P < 0.05). -10 mol / L technetium[ 99 Tc] methylene diphosphonate dispersion capsules, 2×10 -10 mol / L technetium[ 99 Tc] methylene diphosphonate capsules, 2×10 -10 mol / L technetium[ 99 There were no significant differences between the Tc] methylene diphosphonate-coated tablets.

[0305] 3.2 Drugs inhibit osteoclast proliferation

[0306] As shown in Figure 7, compared with the blank group, 2×10 -10 mol / L technetium[ 99 Tc] methylene diphosphonate dispersion capsules, 2×10 -10 mol / L technetium[ 99 Tc] methylene diphosphonate capsules, 2×10 -10 mol / L technetium[ 99 Tc] methylene diphosphonate coated tablets had an inhibitory effect on the proliferation of osteoclasts, and the difference was statistically significant (P < 0.05). -10 mol / L technetium[ 99 Tc] methylene diphosphonate dispersion capsules, 2×10 -10 mol / L technetium[ 99 Tc] methylene diphosphonate capsules, 2×10 -10 mol / L technetium[ 99 There were no significant differences between the Tc] methylene diphosphonate-coated tablets.

[0307] It can be seen that the technetium of the present invention [ 99 Tc] methylene diphosphonate dispersion capsules 2×10 -10 mol / L in vitro on the promotion of osteoblast proliferation and the inhibition of osteoclast proliferation and technetium[ 99 Tc] methylene diphosphonate capsules, technetium [ 99 Tc] methylene diphosphonate coated tablets have comparable effects.

[0308] Test Example 4:

[0309] This experimental example is a test of the technetium [ 99 Tc] methylene diphosphonate dispersion capsules, technetium [ 99 Tc] methylene diphosphonate solid dispersion tablets and prior art technetium [ 99 Tc] methylene diphosphonate coated tablets and ordinary technetium [ 99 Comparison of the toxicity and side effects (in terms of single-dose toxicity) of [Tc] methylene diphosphonate capsules.

[0310] 1 Experimental drug

[0311] 1.1 Test drug

[0312] technetium[ 99 [Tc] Methylene diphosphonate dispersion capsules (same as in Example 5) are ground into very fine powder and dissolved in physiological saline before use. The powder is mixed evenly and diluted to the desired concentration before use.

[0313] technetium[ 99 [Tc] Methylene diphosphonate solid dispersion tablets (same as Example 9) are ground into very fine powder and dissolved in physiological saline before use. The powder is mixed evenly and diluted to the desired concentration before use.

[0314] 1.2 Comparator drugs

[0315] Ordinary technetium[ 99 Tc] methylene diphosphonate capsules, each tablet contains methylene diphosphonate 50 mg, stannous chloride 2 mg, pertechnetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc), anhydrous lactose 185mg, hydroxypropyl cellulose 8mg; colloidal silicon dioxide 2mg; disodium edetate 2mg; magnesium stearate 1mg; Preparation method: ① weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution was dried, it was crushed and passed through an 80-mesh sieve to obtain 99 Tc-MDP complex powder. ② Premix and sieve: weigh the prescribed amount 99The dried Tc-MDP complex powder (passed through a 40-100 mesh sieve and then weighed) was then placed in a suitable PE bag, mixed, and passed through a 40-100 mesh sieve. (3) Mixing: The sieved materials were further placed in a suitable PE bag for mixing. (4) Dry granulation: The mixed materials were dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), using a 1.0 mm sieve mesh size. The pulverized dry granules were collected. (5) Final blending: Magnesium stearate lubricant was added to the dry granules and continued mixing. (6) Capsule filling: The capsules were manually filled according to the target filling amount and sealed. Normal saline was added for uniform mixing before use. The capsules were diluted to the desired concentration immediately before use.

[0316] technetium[ 99 Tc] methylene diphosphonate coated tablets, each tablet contains methylene diphosphonic acid 50 mg; stannous chloride 200 μg, high technetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc); octanoylcarnitine 40mg; microcrystalline cellulose 20mg; sodium carboxymethylcellulose 10mg, silicon dioxide 5mg, magnesium stearate 1mg. Each tablet contains methylcellulose 5mg, polyethylene glycol 400 1mg, iron oxide 1mg, titanium dioxide 1mg, and purified water: 50mg. Preparation method: Weigh the prescribed amount of stannous chloride, add an appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 [Tc] sodium phosphate solution, mix evenly. After drying, crush the solution and pass it through an 80-mesh sieve. Then, mix it with octanoylcarnitine, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, and magnesium stearate, press it into tablets, and coat it. When using, add physiological saline, mix evenly, and dilute to the desired concentration before use.

[0317] 2 Experimental methods

[0318] SPF KM mice were selected and a fixed dose method was used to select 1.0×10 -3 , 1.0×10 -2 , 2.0×10 -2 , 3.0×10 -2 and 4.0×10 -2 mg / kg (all in technetium) were used for the experiment. 1.0×10 -4mg / kg as the initial dose. If there is no obvious toxic reaction, the dose is increased by one level for testing. If animal death or severe toxic reaction occurs, the dose is reduced by one level for testing. If the animal survives at this time, one or several intermediate doses are selected between the two fixed doses for testing. And so on, 3 animals are tested for each dose. 99 Tc] methylene diphosphonate dispersion capsules, technetium [ 99 Tc] methylene diphosphonate solid dispersion tablets, technetium [ 99 Tc] methylene diphosphonate capsules, technetium [ 99 [Tc] methylene diphosphonate coated tablets, single dose, dosing volume: 10 mL / kg. The observation period after administration is at least 7 days. If the animal's toxic reaction still exists on the 7th day, observation is continued for another 7 days. Observation is conducted once a day after administration. Observation indicators include, but are not limited to, the body weight, mortality rate, clinical symptoms (such as animal appearance, behavior, diet, response to stimuli, secretions, excretions, etc.), death (time of death, pre-mortem reaction, etc.) of the test mice. All deaths, symptoms, onset time, severity, duration of symptoms, weight changes, etc. are recorded.

[0319] 3 Experimental results

[0320] When the dosage reaches 4.0×10 -2 mg / kg, ordinary technetium [ 99 Tc] methylene diphosphonate capsules, technetium [ 99 The Tc] methylene diphosphonate coated tablets group had obvious gastrointestinal reactions, manifested as anorexia, nausea, vomiting, abdominal pain or diarrhea, but no deaths occurred; while the technetium [ 99 Tc] methylene diphosphonate dispersion capsule group, technetium [ 99 No obvious gastrointestinal reactions or other drug-related adverse reactions occurred in the Tc-methylene diphosphonate solid dispersion tablets group, and no deaths occurred.

[0321] It can be seen that technetium [ 99 Tc] methylene diphosphonate dispersion capsules, technetium [ 99 The tolerance range of the solid dispersion tablets of methylene diphosphonate is better than that of ordinary technetium [ 99 Tc] methylene diphosphonate capsules, technetium [ 99 Tc] methylene diphosphonate coated tablets have a higher tolerance range and better safety. 99 [Tc] methylene diphosphonate dispersion capsules are rapidly absorbed after oral administration, have high bioavailability, are simple to prepare, reduce the frequency of dosing for patients, and are easy to use. The capsules can also mask the unpleasant odor of the drug and increase the stability of the drug, thereby ensuring safety and greatly improving patient compliance.

[0322] Test Example 5:

[0323] This experimental example is a test of the technetium [ 99 Tc] methylene diphosphonate capsules, technetium [ 99 Tc] methylene diphosphonate solid dispersion tablets and prior art technetium [ 99 Tc] methylene diphosphonate coated tablets and ordinary technetium [ 99 Comparison of the expression of serum inflammatory mediators PGE2 and TNF-α in the CIA rat arthritis model with [Tc] methylene diphosphonate capsules.

[0324] 1 Experimental drug

[0325] 1.1 Test drug

[0326] technetium[ 99 [Tc] Methylene diphosphonate dispersion capsules (same as Experimental Example 5) were ground into very fine powder and dissolved in physiological saline before use. The powder was mixed evenly and diluted to the desired concentration before use.

[0327] technetium[ 99 [Tc] Methylene diphosphonate solid dispersion tablets (same as Experimental Example 9) were ground into very fine powder and dissolved in physiological saline before use. The powder was mixed evenly and diluted to the desired concentration before use.

[0328] 1.2 Comparator drugs

[0329] Ordinary technetium[ 99 Tc] methylene diphosphonate capsules, each tablet contains methylene diphosphonate 50 mg, stannous chloride 2 mg, pertechnetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc), anhydrous lactose 185mg, hydroxypropyl cellulose 8mg; colloidal silicon dioxide 2mg; disodium edetate 2mg; magnesium stearate 1mg; Preparation method: ① weigh the prescribed amount of stannous chloride, add appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 After the solution was dried, it was crushed and passed through an 80-mesh sieve to obtain 99 Tc-MDP complex powder. ② Premix and sieve: weigh the prescribed amount 99The dried Tc-MDP complex powder (passed through a 40-100 mesh sieve and then weighed) was then placed in a suitable PE bag, mixed, and passed through a 40-100 mesh sieve. (3) Mixing: The sieved materials were further placed in a suitable PE bag for mixing. (4) Dry granulation: The mixed materials were dry granulated according to appropriate process parameters (hydraulic pressure, feed speed, roller speed), using a 1.0 mm sieve mesh size. The pulverized dry granules were collected. (5) Final blending: Magnesium stearate lubricant was added to the dry granules and continued mixing. (6) Capsule filling: The capsules were manually filled according to the target filling amount and sealed. Normal saline was added for uniform mixing before use. The capsules were diluted to the desired concentration immediately before use.

[0330] technetium[ 99 Tc] methylene diphosphonate coated tablets, each tablet contains methylene diphosphonic acid 50 mg; stannous chloride 200 μg, high technetium [ 99 Tc] sodium chloride 1 μg (as 99 Tc); octanoylcarnitine 40mg; microcrystalline cellulose 20mg; sodium carboxymethylcellulose 10mg, silicon dioxide 5mg, magnesium stearate 1mg. Each tablet contains methylcellulose 5mg, polyethylene glycol 400 1mg, iron oxide 1mg, titanium dioxide 1mg, and purified water: 50mg. Preparation method: Weigh the prescribed amount of stannous chloride, add an appropriate amount of hydrochloric acid to dissolve, add the prescribed amount of methylene diphosphonic acid, adjust the pH to 5-7 with sodium hydroxide solution, and then add the prescribed amount of pertechnetium [ 99 [Tc] sodium phosphate solution, mix evenly. After drying, crush the solution and pass it through an 80-mesh sieve. Then, mix it with octanoylcarnitine, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, and magnesium stearate, press it into tablets, and coat it. When using, add physiological saline, mix evenly, and dilute to the desired concentration before use.

[0331] 2 Experimental methods

[0332] 2.1 Experimental Animal Modeling and Drug Administration

[0333] SPF grade SD rats, male, weighing (200±20) g. After one week of adaptive feeding, SD rats were randomly divided into 11 groups according to their body weight, namely blank group, model group, ordinary technetium group [ 99 Tc] methylene diphosphonate capsule group (4.0×10 -4 mg / kg), technetium[ 99 Tc] methylene diphosphonate coated tablets (4.0×10 -4 mg / kg), technetium[ 99 Tc] methylene diphosphonate dispersion capsules in low, medium and high dose groups (1.0×10 -4 mg / kg, 2.0×10-4 mg / kg, 4.0×10 -4 mg / kg), technetium[ 99 Tc] methylene diphosphonate solid dispersion tablets low, medium, and high dose groups (1.0×10 -4 mg / kg, 2.0×10 -4 mg / kg, 4.0×10 -4 mg / kg). Except for the blank group, the other groups were all induced to establish CIA rat arthritis model. After the rats that failed to establish the model were eliminated, the ordinary technetium [ 99 The methylene diphosphonate group was given technetium [ 99 Tc] Methylene diphosphonate capsules 4.0×10 -4 mg / kg / d; technetium[ 99 The methylene diphosphonate coated tablet group was given technetium [ 99 Tc] methylene diphosphonate coated tablets 4.0×10 -4 mg / kg / d; technetium[ 99 The low, medium and high dose groups of methylene diphosphonate dispersion capsules were given orally with technetium [ 99 1.0×10 of [Tc] methylene diphosphonate dispersion capsules -4 mg / kg / d, 2.0×10 -4 mg / kg / d, 4.0×10 -4 mg / kg / d; technetium[ 99 The low, medium and high dose groups of methylene diphosphonate solid dispersion tablets were orally gavaged with technetium [ 99 1.0×10 of [Tc] methylene diphosphonate solid dispersion tablets -4 mg / kg / d, 2.0×10 -4 mg / kg / d, 4.0×10 -4 mg / kg / d (all dosages were calculated in technetium); the blank group and the model group were gavaged with equal volumes of normal saline at 24-h intervals, and each group was given the drug continuously for 20 days.

[0334] 2.2 ELISA detection of serum PGE2 and TNF-α levels

[0335] After the administration, blood was collected from the abdominal aorta of the rats, and the serum was separated. The levels of PGE2 and TNF-α in the serum were detected by ELISA. The operation was carried out strictly according to the instructions.

[0336] 3 Experimental results

[0337] Compared with the model group, the normal group, technetium [ 99 Tc] methylene diphosphonate coated tablets, ordinary technetium [ 99Tc] methylene diphosphonate capsule group, technetium [ 99 Tc] methylene diphosphonate dispersion capsules in the middle and high dose groups, technetium [ 99 The levels of serum PGE2 and TNF-α in rats in the medium and high dose groups of Tc] methylene diphosphonate solid dispersion tablets were significantly decreased, and the differences were statistically significant (P<0.05); 99 The serum PGE2 level of rats in the low-dose group of Tc]methylene diphosphonate dispersion tablets showed a downward trend compared with the model group, and there was a significant difference (P<0.05); 99 Tc] methylene diphosphonate dispersion capsule low dose group, technetium [ 99 The serum TNF-α level of rats in the low-dose group of Tc] methylene diphosphonate dispersion tablets showed a downward trend compared with the model group, with no significant difference (P>0.05) (Figures 8 and 9). 99 Tc] methylene diphosphonate coated tablets group, the normal group, model group, 99 Tc] methylene diphosphonate dispersion capsules in the medium / low dose group, technetium [ 99 The serum PGE2 and TNF-α levels of rats in the medium / low dose groups of Tc] methylene diphosphonate solid dispersion tablets were significantly higher than those in the Tc] 99 Tc] methylene diphosphonate coated tablets group, and the difference was statistically significant (P < 0.05). 99 Tc] methylene diphosphonate capsule group, normal group, model group, technetium [ 99 Tc] methylene diphosphonate dispersion capsules in the medium / low dose group, technetium [ 99 The serum PGE2 and TNF-α levels of rats in the medium / low dose groups of Tc] methylene diphosphonate solid dispersion tablets were significantly higher than those in the control group. 99 Tc] methylene diphosphonate capsule group, and the difference was statistically significant (P < 0.05). 99 Tc] methylene diphosphonate capsule group, technetium [ 99 Tc] methylene diphosphonate coated tablets, technetium [ 99 Tc] methylene diphosphonate dispersion capsule high dose group, technetium [ 99 There was no significant difference in the serum PGE2 and TNF-α levels of rats in the high-dose group of Tc-methylene diphosphonate dispersion tablets (P>0.05).

[0338] It can be seen that technetium [ 99 Tc] methylene diphosphonate dispersion capsules (4.0×10 -4 mg / kg), technetium[ 99 Tc] methylene diphosphonate dispersion tablets (4.0×10 -4 mg / kg) may be related to technetium [99 Tc] methylene diphosphonate coated tablets (4.0×10 -4 mg / kg), technetium[ 99 Tc] Methylene diphosphonate capsules (4.0×10 -4 mg / kg) has a comparable effect on reducing the levels of PGE2 and TNF-α in rat serum, and has a good efficacy. 99 Tc] methylene diphosphonate dispersion capsules, technetium [ 99 [Tc] methylene diphosphonate solid dispersion tablets are rapidly absorbed after oral administration, have high bioavailability, and are simple to prepare, reducing dosing frequency and making them convenient to use. The capsules also mask the drug's unpleasant odor and increase its stability, ensuring safety while significantly improving patient compliance. In Figure 8, *P < 0.05 or **P < 0.01 vs. the model group; #P < 0.05 or ##P < 0.01 vs. the standard capsule group; △P < 0.05 or △△P < 0.01 vs. the coated tablet group. In Figure 9, *P < 0.05 or **P < 0.01 vs. the model group; #P < 0.05 or ##P < 0.01 vs. the standard capsule group; △P < 0.05 or △△P < 0.01 vs. the coated tablet group.

[0339] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A kind of technetium 99 Tc] methylene diphosphonate oral preparation, characterized in that The invention is prepared by the following raw materials in parts by weight: Methylene diphosphonic acid: 5 to 200 parts; Reducing agent: 2×10 -3 Servings ~ 20 servings; Technetium [ 99 Tc] sodium salt: 5×10 -5 Servings~5000×10 -5 share; 10 to 1000 parts of adhesive; Solvent 10 parts~1×10 5 share; Wherein, the high-technetium [ 99 Tc] sodium acid weight parts 99 Tc is calculated; the adhesive is made of high molecular polymer material; These include the use of methylene diphosphonic acid, reducing agents, and pertechnetium [ 99 Technetium [ 99 Tc] methylene diphosphonate, and promptly 99 The invention discloses a method for preparing the present invention by dissolving a methylene diphosphonate in a solvent, forming a mixed liquid with an adhesive, and then spray drying the mixed liquid. The outlet temperature of the spray drying process does not exceed 115°C.

2. Technetium according to claim 1 99 Tc] methylene diphosphonate oral preparation, characterized in that The reducing agent is at least one of stannous chloride, stannous fluoride, sodium bisulfite, sodium pyrosulfite, gentisic acid and thiourea dioxide.

3. The technetium according to claim 1 99 Tc] methylene diphosphonate oral preparation, characterized in that The outlet temperature during the spray drying process is 65°C to 115°C.

4. The technetium according to claim 1 99 Tc] methylene diphosphonate oral preparation, characterized in that The adhesive is at least one of a first adhesive and a second adhesive; the first adhesive is at least one of hydroxypropyl methylcellulose, polyethylene glycol polymer, povidone, copovidone, Soluplus, and hydroxypropyl cellulose, and the second adhesive is at least one of hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, trimethylaminoethyl methacrylate copolymer, and polymethacrylate.

5. Technetium according to claim 4 99 Tc] methylene diphosphonate oral preparation, characterized in that The solvent includes at least one of a first solvent and a second solvent; the first solvent is water, and the second solvent is at least one of methanol, ethanol, acetone, and tetrahydrofuran; wherein, when the adhesive used is the first adhesive or a mixed adhesive in which the weight ratio of the first adhesive to the second adhesive is 50:50 to 99:1, the solvent to be used is the first solvent or a mixed solvent in which the weight ratio of the first solvent to the second solvent is 30:70 to 99:1; when the adhesive used is the second adhesive or a mixed adhesive in which the weight ratio of the first adhesive to the second adhesive is 1:99 to 49:51, the solvent to be used is a mixed solvent in which the weight ratio of the first solvent to the second solvent is 5:95 to 70:

30.

6. Technetium according to claim 5 99 Tc] methylene diphosphonate oral preparation, characterized in that It also includes 0.5 to 100 parts of an absorption enhancer, wherein the absorption enhancer includes at least one of a first absorption enhancer and a second absorption enhancer; the first absorption enhancer is at least one of sodium caprate, carboxymethyl chitosan, sodium caprylate, poloxamer-188, sodium laurate sulfate, sodium lauryl sulfate, caprylcarnitine, sodium deoxycholate, carbomer, chitosan, caprylic capric acid macrogol glyceride, and diethylenetriamine pentaacetic acid; the second absorption enhancer is at least one of vitamin E polyethylene glycol succinate, polyoxyethylene 40 hydrogenated castor oil, chitosan oligosaccharide, cell-penetrating peptide, propylene glycol monolaurate, and oleic acid macrogol glyceride; When the adhesive used is the first adhesive or a mixed adhesive in which the weight ratio of the first adhesive to the second adhesive is 50:50 to 99:1, the absorption enhancer to be used is the first absorption enhancer or a mixed absorption enhancer in which the weight ratio of the first absorption enhancer to the second enhancer is 40:60 to 80:20, and the solvent to be used is the first solvent or a mixed solvent in which the weight ratio of the first solvent to the second solvent is 30:70 to 99:1; when the adhesive used is the second adhesive or a mixed adhesive in which the weight ratio of the first adhesive to the second adhesive is 1:99 to 49:51, the absorption enhancer to be used is the second absorption enhancer or a mixed absorption enhancer containing the first absorption enhancer and the second absorption enhancer in a weight ratio of 1:99 to 60:40, and the solvent to be used is a mixed solvent containing the first solvent and the second solvent in a weight ratio of 5:95 to 70:

30.

7. Technetium according to any one of claims 1 to 6 [ 99 Tc] methylene diphosphonate oral preparation, characterized in that It also includes 5 to 500 parts of a diluent, or / and, 10 to 100 parts of a disintegrant, or / and 5 to 50 parts of a lubricant.

8. Technetium according to claim 7 99 Tc] methylene diphosphonate oral preparation, characterized in that The diluent is one or more of pregelatinized starch, microcrystalline cellulose and anhydrous lactose; the disintegrant is one or more of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose; the lubricant is one or more of stearic acid lubricants, talc, micro-powdered silica gel and silicon dioxide.

9. Technetium according to any one of claims 1 to 8 [ 99 Tc] A method for preparing an oral preparation of methylene diphosphonate, characterized in that: The oral preparation is a capsule or tablet, comprising the following steps: Step 1, weighing a reducing agent, adding a hydrochloric acid solution to dissolve it, and obtaining a first mixed material; Step 2, mixing the first mixed material obtained in step 1 with an aqueous solution of methylene diphosphonic acid, and then adding a sodium hydroxide solution to adjust the pH to 5-7 to obtain a second mixed material; Step 3, the second mixed material obtained in step 2 and high technetium [ 99 Tc] sodium acid, dried, crushed, sieved, and obtained technetium [ 99 Tc]methylene diphosphonate; Step 4: The technetium obtained in step 3 99 Tc] methylene diphosphonate is added to the solvent, stirred to dissolve, and the binder is added. Add the absorption enhancer and / or diluent and / or disintegrant together and stir to mix evenly; Step 5: spray-dry the prepared solution, collect the wet solid dispersion from the cyclone separator, dry it, dry granulate it, add a lubricant to mix it, and then fill it into a capsule to obtain a capsule oral preparation; or press it into tablets to obtain oral tablets.

10. Technetium according to any one of claims 1 to 8 [ 99 The application of oral preparations of [Tc] methylene diphosphonates in the treatment of rheumatoid arthritis, ankylosing spondylitis, femoral head necrosis, osteoarthritis, osteoporosis, psoriatic arthritis, bone metastases, and multiple myeloma.

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