A technetium 99 Tc] methylenediphosphonate oral formulation, process for its preparation, use

Abstract

The present invention provides a technetium [ 99 Tc] methylene diphosphonate oral preparation and its preparation method and application, which are prepared from the following raw materials in parts by weight: methylene diphosphonic acid; reducing agent; pertechnetium [ 99 Tc] sodium sulfate; adhesive; solvent; 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 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.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of technetium 99 methylene diphosphonate oral preparations, and in particular to a technetium 99 methylene diphosphonate oral preparation, a preparation method thereof, and an application thereof. BACKGROUND

[0002] Technetium 99 methylene diphosphonate is a chelate formed by the reduction of technetium 99 with stannous chloride and methylene diphosphonate, has the effects of inhibiting the synthesis of prostaglandins and the release of histamine, and can produce anti-inflammatory and analgesic effects, and is mainly used for the treatment of diseases such as rheumatoid arthritis (RA), ankylosing spondylitis, femoral head necrosis, osteoarthritis, osteoporosis, psoriatic arthritis, bone metastases, and multiple myeloma. At present, the disclosed administration methods of technetium 99 methylene diphosphonate 99 (Tc-MDP) mainly include injection administration (preparations including injection liquid preparations and lyophilized powder injections) and oral administration (preparations in the form of ordinary coated tablets).

[0003] The advantage of injection administration is that the drug directly enters the blood circulation system, has high bioavailability and fast onset, but the production process of injections is strict, the cost is high, and the pain during injection, the induration at the injection site, and the inflammation of blood vessels caused by intravenous injection are all problems existing in the clinical application of injections. In addition, technetium 99 methylene diphosphonate injections need to be intravenously dripped, and the patient compliance is poor.

[0004] Chinese patent CN114948890A discloses a preparation for oral administration, i.e., a technetium 99 methylene diphosphonate coated tablet and a preparation method thereof, and the administration route is oral administration, which has the advantage of avoiding injection administration and improving the patient compliance to a certain extent. However, since the main component of the technetium 99 methylene diphosphonate tablet contains a large amount of methylene diphosphonate, the oral tablet of diphosphonate compounds has obvious gastrointestinal irritation and low bioavailability, etc., which leads to poor patient compliance to the coated tablet, and the patient can only use the tablet in the morning, a full cup of white water should be used to send the tablet to the stomach to reduce the stimulation to the esophagus, and the patient should avoid lying down within at least 30 minutes after taking the tablet and before the first meal of the day.

[0005] Therefore, it is of great significance to develop a technetium 99 methylene diphosphonate oral preparation, which can improve the bioavailability, reduce the gastrointestinal irritation, and improve the patient compliance. Summary of the Invention

[0006] 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.

[0007] In order to achieve the above object, the technical solution adopted by the present invention is:

[0008] A technetium 99 The methylene diphosphonate oral preparation is prepared by including the following raw materials in parts by weight:

[0009] Methylene diphosphonic acid: 5 to 200 parts;

[0010] Reducing agent: 2×10 -3 Servings ~ 20 servings;

[0011] Technetium [ 99 Sodium Tc]ate: 5×10 -5 Servings~5000×10 -5 share;

[0012] 10 to 1000 parts of adhesive;

[0013] Solvent 10 parts~1×10 5 share;

[0014] Wherein, the high-technetium [ 99 Tc] sodium sulfate weight parts 99 Tc is calculated; the adhesive is made of high molecular polymer material;

[0015] 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.

[0016] 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 10-20 parts; high pertechnetate 99 5x10 -5 10-5000x10 -5 10-1000 parts; binder 10-1x10 5 10-20 parts; high pertechnetate 99 10-20 parts; high pertechnetate 99 10-20 parts; high pertechnetate 99 Tc] methylenediphosphonate is prepared by using methylenediphosphonic acid, a reducing agent and high pertechnetate 99 Tc] methylenediphosphonate is prepared by using methylenediphosphonic acid, a reducing agent and high pertechnetate 99 Tc] methylenediphosphonate is prepared by using methylenediphosphonic acid, a reducing agent and high pertechnetate 99 Tc] methylenediphosphonate is prepared by using methylenediphosphonic acid, a reducing agent and high pertechnetate 99 Tc] methylenediphosphonate is prepared by using methylenediphosphonic acid, a reducing agent and high pertechnetate 99 Tc] methylenediphosphonate is prepared by using methylenediphosphonic acid, a reducing agent and high pertechnetate

[0017] Further, the reducing agent is at least one of stannous chloride, stannous fluoride, sodium bisulfite, sodium pyrosulfite, gentisic acid and sulfur dioxide.

[0018] Further, the temperature of the air outlet of the spray drying process is 65-115°C.

[0019] Further, the binder is at least one of the first binder and the second binder; the first binder is at least one of hydroxypropyl methylcellulose, polyethylene glycol polymer, povidone, Soluplus, the second binder is at least one of copovidone, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid chloro trimethyl amine ethyl ester copolymer, hydroxypropyl cellulose, polymethacrylate.

[0020] Further, 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; when the adhesive is the first adhesive or a mixed adhesive of the first adhesive and the second adhesive with a weight ratio of 50:50 to 99:1, the solvent used is the first solvent or a mixed solvent of the first solvent and the second solvent with a weight ratio of 30:70 to 99:1; when the adhesive is the second adhesive or a mixed adhesive of the first adhesive and the second adhesive with a weight ratio of 1:99 to 49:51, the solvent used is a mixed solvent of the first solvent and the second solvent with a weight ratio of 5:95 to 70:30.

[0021] The above adaptation can improve the compatibility between raw materials in the preparation process, so that the prepared drug has better permeability.

[0022] Further, the absorption promoter includes at least one of a first absorption promoter and a second absorption promoter; the first absorption promoter is at least one of sodium caprate, carboxymethyl chitosan, sodium caprylate, poloxamer-188, sodium laurate sulfate, sodium dodecyl sulfate, capryl carnitine, sodium deoxycholate, carbomer, chitosan, caprylocaproyl macrogol glycerides, and diethylenetriamine pentaacetic acid; the second absorption promoter is at least one of vitamin E polyethylene glycol succinate, polyoxyethylene 40 hydrogenated castor oil, chitooligosaccharide, transmembrane peptide, propylene glycol monolaurate, and oleic acid polyethylene glycol glyceride; when the adhesive is the first adhesive or a mixed adhesive of the first adhesive and the second adhesive with a weight ratio of 50:50 to 99:1, the absorption promoter used is the first absorption promoter or a mixed absorption promoter of the first absorption promoter and the second absorption promoter with a weight ratio of 40:60 to 80:20, and the solvent used is a mixed solvent of the first solvent and the second solvent with a weight ratio of 30:70 to 99:1; when the adhesive is the second adhesive or a mixed adhesive of the first adhesive and the second adhesive with a weight ratio of 1:99 to 49:51, the absorption promoter used is the second absorption promoter or a mixed absorption promoter of the first absorption promoter and the second absorption promoter with a weight ratio of 1:99 to 60:40, and the solvent used is a mixed solvent of the first solvent and the second solvent with a weight ratio of 5:95 to 70:30.

[0023] The addition of the absorption promoter can increase the liposolubility of the drug and further improve the permeability of the biological membrane of the drug. Meanwhile, the above configuration can cooperate with the adhesive to improve the compatibility and increase the stability of the solution.

[0024] Further, 5-500 parts of diluent, or / and, 10-100 parts of disintegrant, or / and, 5-50 parts of lubricant are further included.

[0025] Further, the diluent is one or more of pre-gelatinized 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 lubricant, talc, micronized silica gel and silicon dioxide.

[0026] Another object of the present application is to provide the above-mentioned technetium 99 Tc] methylene diphosphonate oral preparation.

[0027] Another object of the present application is to provide the above-mentioned technetium 99 Tc] methylene diphosphonate oral preparation.

[0028] Step 1, weigh the reducing agent, add hydrochloric acid solution for dissolution to obtain a first mixture;

[0029] Step 2, mix the first mixture obtained in step 1 with methylene diphosphonic acid aqueous solution, then add sodium hydroxide solution to adjust the pH to 5-7 to obtain a second mixture;

[0030] Step 3, mix the second mixture obtained in step 2 with sodium pertechnetate, dry, crush, sieve to obtain technetium 99 Tc] methylene diphosphonate; 99 Tc] methylene diphosphonate;

[0031] Step 4, add the technetium 99 Tc] methylene diphosphonate obtained in step 3 into a solvent, stir and dissolve, add a binder,

[0032] If an absorption promoter, or / and a diluent, or / and a disintegrant is added, stir and mix uniformly;

[0033] Step 5, spray dry the prepared solution, collect the solid dispersion wet product from the cyclone separator, dry, dry granulation, if the lubricant is added, then mix, and then fill into capsules to obtain capsule oral preparation; or press into tablets to obtain oral tablets.

[0034] The technetium 99 Tc] methylene diphosphonate oral preparation provided by the present application has a simple preparation process and is convenient for popularization and application.

[0035] Another object of the present application is to provide the above-mentioned technetium 99 Tc] methylene diphosphonate oral preparation.

[0036] The above-mentioned technetium 99 The use of the oral preparation of technetium

[0037] Therefore, the present application has the following beneficial effects:

[0038] 1. The present application provides an oral preparation of technetium 99 The oral preparation of technetium -3 The oral preparation of technetium 99 The oral preparation of technetium -5 The oral preparation of technetium -5 The oral preparation of technetium 5 The oral preparation of technetium 99 The oral preparation of technetium 99 The oral preparation of technetium 99 The oral preparation of technetium 99 The oral preparation of technetium 99 The oral preparation of technetium 99 The oral preparation of technetium 99 The oral preparation of technetium 99 The oral preparation of technetium

[0039] 2. The present application provides an oral preparation of technetium 99 The oral preparation of technetium

[0040] 3、The present application provides technetium 99 Use of oral formulations of technetium BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 Drug concentration-time curves for Example 1 and Comparative Example 1.

[0042] Figure 2 Sample chart prepared for Comparative Example 3.

[0043] Figure 3 Drug dissolution curves for Tc in different formulations in pH 6.8 medium in Test Example 1. 99 Drug dissolution curves for Tc in different formulations in pH 6.8 medium in Test Example 1.

[0044] Figure 4 Drug dissolution curves for MDP in different formulations in pH 6.8 medium in Test Example 1.

[0045] Figure 5 Drug concentration-time curves for Test Example 2.

[0046] Figure 6 Effect of the drug on the proliferation of rat neonatal osteoblasts in Test Example 3 (x ± s, n = 6).

[0047] Figure 7 Effect of the drug on the proliferation of rat neonatal osteoclasts in Test Example 3 (x ± s, n = 6).

[0048] Figure 8 Effect of the drug on the serum PGE2 level in rats in Test Example 5 (x ± s, n = 8-10).

[0049] Figure 9 Effect of the drug on the serum TNF-α level in rats in Test Example 5 (x ± s, n = 8-10). n = 8-10). DETAILED DESCRIPTION

[0050] The present application will be described in detail below with reference to the accompanying drawings.

[0051] In order to make the objectives, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific examples described herein are only used to explain the present application and do not limit the present application.

[0052] In the following examples and comparative examples, the specifications of some of the raw materials involved are shown in Table 1.

[0053] Table 1

[0054]

[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 Tc]Methylene diphosphonate powder injection. At 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 12 h after each drug, 3 rats were selected from each group, and the abdominal aorta of the rats was quickly dissected to extract whole blood. After anticoagulation, the plasma was separated by centrifugation and treated.

[0083] 2.2 Sample treatment

[0084] The whole blood was extracted from the abdominal aorta of rats, and the plasma was separated by centrifugation after sodium citrate anticoagulation. 0.8 mL of plasma was taken, 1.8 mL of 30% hydrochloric acid was added for digestion, and after complete digestion of the plasma, 0.65 mL was taken and diluted to 6.5 mL with 0.1% Triton 100 (purified water) and filtered with a 0.22 μm filter. Then 5 mL was introduced into the ICP-MS to determine the response value.

[0085] 2.3 Data analysis

[0086] DAS 2.1.1 software was used for pharmacokinetic analysis. The following formula was used to calculate the absolute bioavailability F = AUC 口服 / AUC 静脉 × 100%.

[0087] 3 Experimental results

[0088] The series sampling time and rat plasma concentration were plotted into a concentration-time curve, and the results are shown in Figure 1 The main pharmacokinetic parameters of each group were calculated by 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 concentration-time 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%. Therefore, compared with Comparative Example 1, the exposure and bioavailability of Example 1 in rats were slightly increased.

[0089] Table 2 Main pharmacokinetic parameters in rats

[0090] Pharmacokinetic parameters Example 1 Comparative Example 1 Powder injection group Cmax (pg / mL) 0.0099±0.150 0.0079±0.13 6.423±0.136 Tmax (h) 1.0 1.0 0.083 t1 / 2 (h) 7.23 6.90 0.55 AUC (0-t) (μg / mL*h) 0.049 0.041 3.440 Bioavailability F% 1.42 1.19 -

[0091] Comparative Example 2

[0092] Comparative Example 2 did not change the raw material relative to Example 1, and the only difference was that spray drying was not used, and the others were unchanged.

[0093] Filler prescription:

[0094] Methylene diphosphonate: 50 g;

[0095] Stannous chloride: 2 g;

[0096] Technetium [ 99 Sodium Tc]ate: 1×10 -3 g(with 99 Tc meter);

[0097] Copolyvidone VA64: 100g

[0098] Magnesium stearate: 1g;

[0099] 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 [ 99 Tc] 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.

[0100] 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.

[0101] 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.

[0102] The specific configuration method is as follows:

[0103] Background solution: other ingredients except technetium (configuration according to the amount of 50 parts of unit dose sample), MDP, SnCl2, NaOH (solution conditioning neutral), precise weighing, add a certain volume of water for injection to completely dissolve, concentrate to about 50 mL under the condition of micro-boiling water, after cooling to room temperature, add 100 mL H2O2, mix well, stand for 10 min, concentrate under the condition of micro-boiling, when concentrated to near powder state, water bath dry. Again, bake at 105℃ for no less than 2h to remove H2O2, dissolve with water, transfer to a 100mL volumetric flask, dilute to the mark, ready for use.

[0104] Standard working curve: use a pipette to accurately measure a certain amount of high-concentration 99 Tc solution to a 10mL volumetric flask, dilute to the mark with water for injection, shake well, and get a Tc solution with a concentration of about 10μg / mL. 99

[0105] Use a pipette to accurately measure 9.4mL of sample background solution, take 6 parts, and place them in 10mL volumetric flasks respectively. Add 10μg / mL TcO 4- solution to the labeled beakers, 0.05mL, 0.10mL, 0.15mL, 0.20mL, 0.25mL, 0.30mL, dilute to 10mL with water for injection, get 99 Tc series standard curve solution (0.05μg / mL, 0.10μg / mL, 0.15μg / mL, 0.20μg / mL, 0.25μg / mL, 0.30μg / mL) for HPLC detection.

[0106] The 99 Tc content HPLC detection data are shown in Table 3. As can be seen from Table 3, the technetium content of the preparation of Example 1 is 98.3%, which is significantly higher than the technetium content of 48.5% of Comparative Example 2, indicating that 99 Tc complex solution is not stable at high temperature for a long time, and needs to be quickly converted from solution to solid state.

[0107] Table 3 Tc content detection results of preparation 99

[0108] Group Example 1 Comparative Example 2 99 Tc content ​ 98.3％ 48.5％

[0109] Comparative Example 3

[0110] Comparative Example 3 changes the outlet temperature of the spray drying to 55℃, while the raw materials remain unchanged compared with Example 1.

[0111] Filler prescription:

[0112] Methylene diphosphonic acid: 50g;

[0113] ​​Stannous chloride: 2g;

[0114] Technetium [ 99 Sodium Tc]ate: 1×10 -3 g(with 99 Tc meter);

[0115] Copolyvidone VA64: 100g

[0116] 30% ethanol solution: 3000g;

[0117] Magnesium stearate: 1g;

[0118] 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.

[0119] When the air outlet temperature is around 55℃, the sample obtained is a hard block (such as Figure 2 As shown in the figure, considering that purified water, a solvent, does not fully evaporate at low outlet temperatures, resulting in a large amount of powder adhering to the inner walls of the drying tower and cyclone separator. This results in a relatively low final yield of the complex, only 45%, and a high moisture content of around 12%. Therefore, adjusting the outlet temperature to around 75°C resulted in a loose complex, meeting experimental requirements. To further reduce the moisture content of the complex, the outlet temperature was controlled at 80°C and 85°C, which reduced the moisture content of the final product to around 8%, increasing the final yield to 57%.

[0120] Example 2:

[0121] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0122] Filler prescription:

[0123] Methylene diphosphonic acid: 50g;

[0124] Stannous chloride: 2g;

[0125] Technetium [ 99 Sodium Tc]ate: 1×10 -3 g(with 99 Tc meter);

[0126] Copolyvidone VA64: 100g

[0127] 30% ethanol solution: 3000g;

[0128] Magnesium stearate: 1g;

[0129] 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 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.

[0130] Example 3

[0131] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0132] Filler prescription:

[0133] Methylene diphosphonic acid: 50g;

[0134] Stannous chloride: 2g;

[0135] Technetium [ 99 Sodium Tc]ate: 1×10 -3 g(with 99 Tc meter);

[0136] Povidone K30: 100g

[0137] Sodium caprate: 20g

[0138] 30% ethanol solution: 3000g;

[0139] Magnesium stearate: 1g;

[0140] 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.

[0141] Example 4

[0142] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0143] Filler prescription:

[0144] Methylene diphosphonic acid: 5g;

[0145] Stannous chloride: 2×10 -3 g;

[0146] Sodium bisulfite: 0.1g;

[0147] Technetium [ 99 Sodium tc]ate: 5×10 -5 g(with 99 Tc meter);

[0148] Macrogol 2000: 2g

[0149] Hydroxypropyl methylcellulose acetate succinate: 160g

[0150] Sodium caprate: 1g

[0151] Propylene glycol monolaurate: 1g

[0152] Magnesium stearate: 3g

[0153] Water-acetone-tetrahydrofuran solution (2:3:5): 2000g

[0154] 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.

[0155] Example 5

[0156] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0157] Filler prescription:

[0158] Methylene diphosphonic acid: 200g;

[0159] Gentisic acid: 1g;

[0160] Technetium [ 99 Tc] sodium chloride: 0.05g (in 99 Tc meter);

[0161] Soluplus: 25g

[0162] Carbomer: 3g

[0163] Magnesium stearate: 1g

[0164] 25% acetone solution: 3000g

[0165] 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.

[0166] Example 6

[0167] Preparation of technetium[ 99 Tc] Methylene diphosphonate solid dispersion capsules (1000 capsules)

[0168] Filler prescription:

[0169] Methylene diphosphonic acid: 100g;

[0170] Stannous chloride: 5g;

[0171] Technetium [ 99 Sodium tc]ate: 2×10 -3 g(with 99 Tc meter);

[0172] Hydroxypropyl methylcellulose acetate succinate: 25g

[0173] Polymethacrylate: 5g

[0174] Chitosan oligosaccharide: 20g

[0175] Oleic acid macrogol glycerides: 10g

[0176] Silicon dioxide: 1g

[0177] 50% tetrahydrofuran solution: 4000g

[0178] 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 crushing screen size is 1.0 mm. The crushed dry granules are collected. The prescribed amount of magnesium stearate is added to the dry granules and continued to be manually mixed for 3 minutes. The granules are filled into the prepared hydroxypropyl methylcellulose capsules according to the target loading amount.

[0179] Example 7: Technetium of the present invention [ 99 [Tc] Methylene diphosphonate solid dispersion tablets (1000 tablets)

[0180] Methylene diphosphonic acid: 100g;

[0181] Stannous chloride: 0.25g;

[0182] Technetium [ 99 Sodium tc]ate: 2.5×10 -4 g(with 99 Tc meter);

[0183] Copolyvinylpyrrolidone-VA64: 15g

[0184] Sodium lauryl sulfate: 15g

[0185] 35% acetone solution: 3000g

[0186] Microcrystalline cellulose: 100g;

[0187] Magnesium stearate: 2g;

[0188] Micro powder silica gel: 1g;

[0189] 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. 99The 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.

[0190] Example 8: Technetium of the present invention [ 99 [Tc] Methylene diphosphonate solid dispersion tablets (1000 tablets)

[0191] Methylene diphosphonic acid: 5g;

[0192] Stannous chloride: 2×10 -3 g;

[0193] Sodium bisulfite: 0.1g;

[0194] Technetium [ 99 Sodium Tc]ate: 5×10 -5 g(with 99 Tc meter);

[0195] Hydroxypropyl cellulose: 100g

[0196] 60% methanol solution: 3000g

[0197] Caprylic / capric macrogol glycerides: 25g

[0198] Microcrystalline cellulose: 10g;

[0199] Sodium carboxymethyl starch: 10g;

[0200] Magnesium stearate: 0.5g;

[0201] Talc: 1g;

[0202] 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. 99The 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.

[0203] Example 9: Technetium of the present invention [ 99 [Tc] Methylene diphosphonate solid dispersion tablets (1000 tablets)

[0204] Methylene diphosphonic acid: 200g;

[0205] Stannous chloride: 1g;

[0206] Technetium [ 99 Sodium Tc]ate: 1×10 -3 g(with 99 Tc meter);

[0207] Trimethylaminoethyl methacrylate copolymer: 10g

[0208] Hydroxypropyl cellulose: 20g

[0209] Sodium deoxycholate: 2g

[0210] Vitamin E polyethylene glycol succinate: 1g

[0211] 55% tetrahydrofuran solution: 2500g

[0212] Anhydrous lactose: 20g;

[0213] Magnesium stearate: 2g;

[0214] 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. 99The 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 granulated granules and continued to be manually mixed for 3 minutes. The tablets were directly compressed to obtain the tablets.

[0215] Example 10: Technetium of the present invention [ 99 [Tc] Methylene diphosphonate solid dispersion tablets (1000 tablets)

[0216] Methylene diphosphonic acid: 50g;

[0217] Stannous chloride: 0.25g;

[0218] Ascorbic acid: 0.25g;

[0219] Technetium [ 99 Sodium tc]ate: 2.5×10 -4 g(with 99 Tc meter);

[0220] Hydroxypropyl cellulose: 80g

[0221] Hydroxypropyl methylcellulose phthalate: 20g

[0222] Vitamin E polyethylene glycol succinate: 2g

[0223] Propylene glycol monolaurate: 4g

[0224] 45% acetone solution: 2000g

[0225] Pregelatinized starch: 150g;

[0226] Sodium carboxypropyl starch: 8g;

[0227] Magnesium stearate: 1g;

[0228] Silicon dioxide: 0.1g;

[0229] 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 [ 99Tc] 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.

[0230] Test Example 1:

[0231] 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.

[0232] 1 Experimental drug

[0233] 1.1 Test drug

[0234] technetium[ 99 Tc] Methylene diphosphonate dispersion capsules (same as Example 2)

[0235] technetium[ 99 Tc] methylene diphosphonate solid dispersion tablets (same as Example 8).

[0236] 1.2 Comparator drugs

[0237] 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 [ 99After 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.

[0238] 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.

[0239] 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.

[0240] 2 Experimental methods

[0241] 2.1 Dissolution testing

[0242] 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.

[0243] Dissolution test method: The dissolution data of the capsules were determined by the paddle method (with a sinker) under the condition of 500 mL, pH 6.8, 50 rpm, and the sampling points were 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 75 min, 90 min, and 120 min (limiting speed 250 rpm, 15 min).

[0244] 2.2 99 Tc detection:

[0245] Linear solution: 99 Tc standard solution (10 mg / L): 0.9 ml of Na 99 TcO4 solution was transferred to a 10 ml volumetric flask, diluted with purified water to the calibration line, and shaken well.

[0246] Stock solution: 0.1 ml of Tc standard solution (10 mg / L) was diluted to 10 ml with diluent and shaken well.

[0247] The stock solution was diluted to 10 ml with diluent according to Table 4 and shaken well.

[0248] Table 4

[0249] Name STD 1 STD 2 STD 3 STD 4 STD 5 Stock solution (ml) 0.01 0.05 0.1 0.5 1 Concentration (ng / ml) 0.1 0.5 1 5 10

[0250] Preparation of test sample solution: One sample capsule was taken, and the sample was taken at each time point according to the dissolution and release test method (Chinese Pharmacopoeia 2020 edition four general rules 0931 second method) under the above dissolution conditions. The sample was injected into ICP-MS according to the "ICP-MS method".

[0251] 2.3 MDP detection

[0252] UPLC chromatographic conditions

[0253]

[0254] MS File

[0255]

[0256] MS Tune File

[0257] Type MRM (ES-) Capillary (KV) 3 Cone (V) 20 Source Temperature (°C) 320 Cone Gas Flow 0 Desolvation Gas Flow (L / Hr) 550 Collision energy 4

[0258] Solution preparation:

[0259] Preparation of mobile phase A (5 mmol / L ammonium formate solution): 0.316 g of ammonium formate was weighed into 1 L of ultrapure water, dissolved, mixed, filtered through a water-based microporous filter, and ultrasonicated.

[0260] Preparation of mobile phase B: Measure 2 L of methanol and filter it through a microporous filter membrane, then ultrasonicate.

[0261] 3 Experimental results

[0262] Test results such as Figure 3 and Figure 4 shown.

[0263] 3.1 99 Tc calibration curve linear results:

[0264] Analyte Mass Curve Type Slope Intercept Corr. Coeff Tc 99.000 Simple Linear 5845.23 -96.52 0.999894

[0265] Table 5 pH 6.8 medium 99 Tc dissolution results

[0266]

[0267] 3.2 MDP Detection

[0268] The in vitro dissolution results of MDP are shown in Table 6 below

[0269] Table 6 Dissolution results of MDP in pH 6.8 medium

[0270]

[0271] Test Example 2:

[0272] 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.

[0273] 1 Experimental drug

[0274] 1.1 Test drug

[0275] 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.

[0276] 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.

[0277] 1.2 Comparator drugs

[0278] Ordinary technetium[ 99Tc] methylene diphosphonate capsules, each containing 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.

[0279] 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.

[0280] technetium[ 99Tc]Methylene diphosphonate powder injection (same as the example 2 of Chinese patent CN103203032B), mixed uniformly, diluted to the required concentration before use.

[0281] 2 Experimental method

[0282] 2.1 Dosing regimen and sample collection

[0283] Take 135 SD rats which have been fasted overnight, and randomly divide into five groups, respectively, and give 4.0×10 -4 mg / kg (calculated by technetium) technetium 99 Tc]Methylene diphosphonate dispersion capsule, 4.0×10 -4 mg / kg (calculated by technetium) technetium 99 Tc]Methylene diphosphonate dispersion tablet, 4.0×10 -4 mg / kg (calculated by technetium) technetium 99 Tc]Methylene diphosphonate capsule, 4.0×10 -4 mg / kg (calculated by technetium) technetium 99 Tc]Methylene diphosphonate coated tablet and tail vein injection 4.0×10 -4 mg / kg (calculated by technetium) technetium 99 Tc]Methylene diphosphonate powder injection. At 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 12 h after each drug, select 3 rats from each group, quickly dissect the abdominal aorta to extract whole blood, and centrifuge the plasma after anticoagulation.

[0284] 2.2 Sample processing

[0285] Extract whole blood from the abdominal aorta of rats, centrifuge the plasma after sodium citrate anticoagulation, take 0.8 mL of plasma, add 1.8 mL of 30% hydrochloric acid for digestion, after complete digestion of the plasma, take out 0.65 mL and dilute to 6.5 mL with 0.1% Triton 100 (purified water), and then pass through a 0.22 μm filter, and take 5 mL for ICP-MS determination of response value.

[0286] 2.3 Data analysis

[0287] Use DAS2.1.1 software for pharmacokinetic analysis. The following formula is used to calculate the absolute bioavailability F = AUC 胶囊 / 片剂 / AUC 粉针剂 × 100%.

[0288] 3 Experimental results

[0289] Draw the concentration-time curve of the series of sampling time and rat plasma, and the results are as follows Figure 5The 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%.

[0290] 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.

[0291] Table 7 Main pharmacokinetic parameters in rats

[0292]

[0293]

[0294] Test Example 3:

[0295] 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 [ 99Comparison of the efficacy of Tc]methylene diphosphonate capsules (effects on osteoblasts and osteoclasts in vitro).

[0296] 1 Experimental drug

[0297] 1.1 Test drug

[0298] 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.

[0299] 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.

[0300] 1.2 Comparator drugs

[0301] Ordinary technetium[ 99 Tc] methylene diphosphonate capsules, each containing 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 granulated 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 and diluted to the desired concentration before use.

[0302] technetium[ 99 Tc] methylene diphosphonate coated tablets, each tablet contains methylene diphosphonic acid 50 mg; stannous chloride 200 μg, high technetium [99 Tc] sodium 1 μg (as Tc) 99 Octanoyl carnitine 40 mg; microcrystalline cellulose 20 mg; sodium carboxymethyl cellulose 10 mg, silicon dioxide 5 mg, magnesium stearate 1 mg. The coating prescription contains methyl cellulose 5 mg, polyethylene glycol 400 1 mg, iron oxide 1 mg, titanium white powder 1 mg, purified water: 50 mg per tablet. Preparation method: the prescription amount of stannous chloride is weighed, dissolved in an appropriate amount of hydrochloric acid, then the prescription amount of methylene diphosphonic acid is added, the pH is adjusted to 5-7 with sodium hydroxide solution, and then the prescription amount of sodium pertechnetate solution is added and mixed uniformly. After drying the solution, it is crushed and passed through an 80 mesh sieve. Then mix with octanoyl carnitine, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, magnesium stearate, press into tablets, and coat, to obtain the product. When used, add normal saline and mix uniformly, and dilute to the required concentration before use. 99 Tc] sodium solution, mix uniformly. After drying the solution, crush and pass through an 80 mesh sieve. Then mix with octanoyl carnitine, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, magnesium stearate, press into tablets, and coat, to obtain the product. When used, add normal saline and mix uniformly, and dilute to the required concentration before use.

[0303] 1.3 Experimental cells

[0304] 1.3.1 Isolation and culture of osteoblasts

[0305] Under sterile conditions, the calvaria of newborn SD rat pups was taken, the connective tissue and periosteum were removed, the bone pieces were cut and digested with enzymes, the digested solution was discarded, and the cells were resuspended in DMEM high glucose medium containing 10% fetal bovine serum and transferred to culture dishes, which were incubated in a 37°C, 5% CO2 incubator. The identification results showed that both alkaline phosphatase and calcified nodule staining were positive. From P2 cells, osteogenic induction medium was used for culture, and P3-P5 cells were used for subsequent experiments.

[0306] 1.3.2 Isolation and culture of osteoclasts

[0307] Under sterile conditions, the long bones of SD rat pups were taken, the soft tissue on the surface of the bone and the epiphysis were removed, the bone marrow cavity and the inner surface of the bone were repeatedly washed in α-MEM complete medium, and the bone marrow suspension was filtered with a 200 mesh cell sieve. The filtered cell suspension was evenly inoculated into culture bottles, which were incubated in a 37°C, 5% CO2 incubator, and induced with M-CSF and RANKL. RACP staining was positive.

[0308] 2 Experimental method

[0309] 2.1 MTT method for determining osteoblast proliferation

[0310] Logarithmic growth phase osteoblasts were inoculated in 96-well cell culture plates at a density of 2×10 4 / mL, 100 μL per well, and incubated in a 37°C, 5% CO2 incubator for 24 h. Then they were divided into 4 groups, each group was replaced with blank culture medium, 2×10 - 10 mol / L (as Tc)99 Tc) technetium 99 Tc] methylene diphosphonate dispersion capsule, 2 x 10 -10 mol / L (as 99 Tc) technetium 99 Tc] methylene diphosphonate dispersion tablet, 2 x 10 -10 mol / L (as 99 Tc) technetium 99 Tc] methylene diphosphonate capsule, 2 x 10 -10 mol / L (as 99 Tc) technetium 99 Tc] methylene diphosphonate coated tablet culture medium, each group was set up 6 duplicate wells, after 24h of drug culture. Before the end of cell culture, add MTT (5g / L) 40μL per well, continue to incubate for 4h. Absorb the supernatant in the well, add DMSO 150μL per well, shake for 10min, detect the absorbance (OD value) of each well at 490nm wavelength.

[0311] 2.2 MTT assay of osteoclast proliferation cells

[0312] Logarithmic growth period of osteoclasts were inoculated in 96-well cell culture plates at a density of 2 x 10 4 / mL, 100μL per well, after 24h of culture in 37℃, 5% CO2 incubator, divided into 4 groups, each group was replaced with blank culture medium, containing 2 x 10 - 10 mol / L (as 99 Tc) technetium 99 Tc] methylene diphosphonate dispersion capsule, 2 x 10 -10 mol / L (as 99 Tc) technetium 99 Tc] methylene diphosphonate capsule, 2 x 10 -10 mol / L (as 99 Tc) technetium 99 Tc] methylene diphosphonate coated tablet culture medium, each group was set up 6 duplicate wells, after 24h of drug culture. Before the end of cell culture, add MTT (5g / L) 40μL per well, continue to incubate for 4h. Absorb the supernatant in the well, add DMSO 150μL per well, shake for 10min, detect the absorbance (OD value) of each well at 490nm wavelength.

[0313] 3 Experimental results

[0314] 3.1 Drug promotes the proliferation of osteoblasts

[0315] As Figure 6 shown, compared with the blank group, 2 x 10 -10mol / L technetium 99 Tc] methylene diphosphonate dispersion capsule, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate dispersion tablet, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate capsule, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate coated tablet, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate dispersion capsule, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate capsule, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate coated tablet, 2 x 10

[0316] 3.2 Drug inhibits the proliferation of osteoclasts

[0317] As Figure 7 shown, compared with the blank group, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate dispersion capsule, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate capsule, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate coated tablet, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate dispersion capsule, 2 x 10 -10 mol / L technetium 99 Tc] methylene diphosphonate capsule, 2 x 10 - 10 mol / L technetium 99 Tc] methylene diphosphonate coated tablet, 2 x 10

[0318] It can be seen that the technetium 99 Tc] methylene diphosphonate dispersion capsule 2 x 10 -10 mol / L has the promoting proliferation effect on osteoblasts in vitro and the inhibiting effect on the proliferation of osteoclasts, and the technetium 99 Tc] methylene diphosphonate capsule, technetium 99Tc] methylene diphosphonate coated tablets have comparable effects.

[0319] Test Example 4:

[0320] 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.

[0321] 1 Experimental drug

[0322] 1.1 Test drug

[0323] 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.

[0324] 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.

[0325] 1.2 Comparator drugs

[0326] Ordinary technetium[ 99 Tc] methylene diphosphonate capsules, each containing 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 99Tc-MDP complex powder (after 40-100 mesh sieve and then weighed), dry, hydroxypropyl cellulose, colloidal silicon dioxide, disodium edetate (after 40-100 mesh sieve and then weighed) are placed in a suitable PE bag in turn and mixed after 40-100 mesh sieve; ③ mixing: the sieved material is continuously placed in a suitable PE bag for mixing; ④ dry granulation: the mixed material is dry granulated according to the appropriate process parameters (hydraulic, feed speed, roller speed), the size of the crushing screen is 1.0 mm, and the dry granules after crushing are collected; ⑤ total mixing: magnesium stearate lubricant is added to the dry granulated particles for continuous mixing; ⑥ capsule filling: manual filling of capsules is performed according to the target filling amount, and locking is performed. When used, add normal saline and mix evenly, and dilute to the required concentration before use.

[0327] Technetium 99 Tc] methylene diphosphonate coated tablets, each containing 50 mg of methylene diphosphonate; 200 μg of stannous chloride, 1 μg of sodium pertechnetate [Technetium 99 Tc] (as Technetium 99 Tc); 40 mg of capryl carnitine; 20 mg of microcrystalline cellulose; 10 mg of sodium carboxymethyl cellulose, 5 mg of silicon dioxide, and 1 mg of magnesium stearate. The coating prescription contains 5 mg of methyl cellulose, 1 mg of polyethylene glycol 400, 1 mg of iron oxide, 1 mg of titanium white powder, and 50 mg of purified water per tablet. Preparation method: the prescribed amount of stannous chloride is dissolved by adding an appropriate amount of hydrochloric acid, then the prescribed amount of methylene diphosphonate is added, the pH is adjusted to 5-7 with sodium hydroxide solution, and then the prescribed amount of sodium pertechnetate [Technetium 99 Tc] solution is added and mixed evenly. The solution is dried, crushed, and sieved through an 80-mesh sieve. Then it is mixed with capryl carnitine, microcrystalline cellulose, sodium carboxymethyl starch, silicon dioxide, and magnesium stearate, and then tableted and coated, to obtain the product. When used, add normal saline and mix evenly, and dilute to the required concentration before use.

[0328] 2 Experimental method

[0329] SPF KM mice were selected, and a fixed dose method was used to select five fixed doses of 1.0×10 -3 , 1.0×10 -2 , 2.0×10 -2 , 3.0×10 -2 and 4.0×10 -2 mg / kg (all as technetium). From the above five doses, 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.

[0330] 3 Experimental results

[0331] 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.

[0332] 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.

[0333] Test Example 5:

[0334] 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.

[0335] 1 Experimental drug

[0336] 1.1 Test drug

[0337] 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.

[0338] 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.

[0339] 1.2 Comparator drugs

[0340] Ordinary technetium[ 99 Tc] methylene diphosphonate capsules, each containing 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.

[0341] 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.

[0342] 2 Experimental methods

[0343] 2.1 Experimental Animal Modeling and Drug Administration

[0344] 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 x 10 -4 mg / kg), technetium 99 mg / kg, 4.0 x 10 -4 mg / kg, 2.0 x 10 -4 mg / kg, 4.0 x 10 -4 mg / kg). Except the blank group, the rest groups were made into CIA rats arthritis model, and the rats which were not made into model were removed. The normal technetium 99 mg / kg, 4.0 x 10 99 mg / kg / d; the technetium -4 mg / kg / d; the technetium 99 mg / kg / d; the technetium 99 mg / kg / d; the technetium -4 mg / kg / d; the technetium 99 mg / kg / d; the technetium 99 mg / kg / d, 2.0 x 10 -4 mg / kg / d, 4.0 x 10 -4 mg / kg / d; the technetium -4 mg / kg / d; the technetium 99 mg / kg / d; the technetium 99 mg / kg / d, 2.0 x 10 -4 mg / kg / d, 4.0 x 10 -4 mg / kg / d; the technetium -4 mg / kg / d (the dosages were all calculated based on technetium); the blank group and the model group were given the same volume of normal saline at an interval of 24 h, and each group was continuously given the drug for 20 days.

[0345] 2.2 ELISA method was used to detect the levels of PGE2 and TNF-α in serum

[0346] After the administration was completed, the blood was taken 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, and the operation was strictly performed according to the instruction manual.

[0347] 3 Experimental results

[0348] Compared with the model group, the normal group, the technetium 99 mg / kg, 4.0 x 10 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) ( Figure 8 、 9 ). and technetium[ 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).

[0349] 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) can be equivalent to technetium 99 Tc] methylene diphosphonate coated tablets (4.0 x 10 -4 mg / kg), the effect of technetium 99 Tc] methylene diphosphonate capsules (4.0 x 10 -4 mg / kg) on reducing the levels of serum PGE2 and TNF-α in rats is equivalent, and the drug efficacy is good. Meanwhile, the technetium 99 Tc] methylene diphosphonate dispersion capsules and the technetium 99 Tc] methylene diphosphonate solid dispersion tablets of the present application are rapidly absorbed after oral administration, have high bioavailability, simple preparation process, low administration frequency, and are convenient to use. The capsules can also mask the bad smell of the drug, increase the stability of the drug, ensure safety, and greatly improve the compliance of patients. Among them, Figure 8 *P<0.05 or **P<0.01 vs model group; #P<0.05 or ##P<0.01 vs common capsule group; △P<0.05 or △△P<0.01 vs coated tablet group. Among them, Figure 9 *P<0.05 or **P<0.01 vs model group; #P<0.05 or ##P<0.01 vs common capsule group; △P<0.05 or △△P<0.01 vs coated tablet group.

[0350] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement, and improvement within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A kind of technetium 99 Tc] methylene diphosphonate oral preparation, characterized in that According to parts by weight, the following raw materials are prepared become, Methylene diphosphonic acid: 5 to 200 parts; Reducing agent: 2×10 -3 Servings~20 servings; Technetium [ 99 Sodium tc]ate: 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 hydroxide parts by weight 99 Tc is calculated; the adhesive is made of high molecular polymer material; Among them, the use of methylene diphosphonic acid, reducing agents and high-technetium [ 99 Technetium [ 99 Tc] methylene diphosphonate, and promptly 99 The solid dispersion is prepared by dissolving a methylene diphosphonate in a solvent and a binder to form a mixed solution, and then spray drying the mixed solution. The outlet temperature of the spray drying process is 65° C. to 115° C. 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.

2. The 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 and thiourea dioxide.

3. The technetium according to claim 1 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 50:50~99:1, 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 30:70~99:1; 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 1:99~49:51, the solvent to be used is a mixed solvent in which the weight ratio of the first solvent to the second solvent is 5:95~70:

30.

4. The technetium according to claim 3 99 Tc] methylene diphosphonate oral preparation, characterized in that The invention 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, sodium caprylate, sodium lauryl sulfate, capryloylcarnitine, sodium deoxycholate, carbomer, chitosan, and caprylic acid capric macrogol glyceride; the second absorption enhancer is at least one of vitamin E polyethylene glycol succinate, polyoxyethylene 40 hydrogenated castor oil, propylene glycol monolaurate, and oleic acid macrogol glyceride; When the adhesive is the first adhesive or a mixed adhesive with the first adhesive and the second adhesive in a weight ratio of 50:50 to 99:1 When the absorption enhancer is used, the absorption enhancer to be used is the first absorption enhancer or the weight ratio of the first absorption enhancer to the second absorption enhancer is The mixed absorption promoter of 40:60~80:20 should use the first solvent or the first solvent and the second solvent in a weight ratio of When the binder is the second binder or a mixed binder in which the weight ratio of the first binder to the second binder is 1:99 to 49:51, the absorption enhancer to be used is the second absorption enhancer or a mixed absorption enhancer comprising 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 comprising the first solvent and the second solvent in a weight ratio of 5:95 to 70:

30.

5. Technetium according to any one of claims 1 to 4 99 Tc] methylene diphosphonate oral preparation, characterized in that The composition 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.

6. Technetium according to claim 5 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 and silicon dioxide.

7. Technetium according to any one of claims 1 to 6 99 The method for preparing a methylene diphosphonate oral preparation is characterized in that: Oral preparations are capsules or tablets and include the following steps: Step 1: Weigh a reducing agent, add hydrochloric acid solution to dissolve it, and obtain 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 is mixed with high-technetium [ 99 Tc] sodium salt, 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 a binder is added, and if present, an absorption enhancer and / or a diluent and / or a disintegrant are added together, and stirred to mix uniformly; Step 5: spray-dry the prepared solution, collect the wet solid dispersion from the cyclone separator, dry it, and Granulate, if there is a lubricant, add the lubricant and mix, then fill into capsules to obtain capsule oral preparations; or tablet, to obtain oral tablet.

8. Technetium according to any one of claims 1 to 6 99 Application of [Tc] methylene diphosphonate oral preparation in the preparation of drugs for treating rheumatoid arthritis, ankylosing spondylitis, femoral head necrosis, osteoarthritis, osteoporosis, psoriatic arthritis, bone metastasis and multiple myeloma.

Images