Preparation method for sitagliptin phosphate resin sustained-release microcapsule and use thereof

Abstract

The present invention pertains to the technical field of pharmaceuticals and relates to a preparation method for a sitagliptin phosphate resin sustained-release microcapsule and use thereof. The sitagliptin phosphate resin sustained-release microcapsule comprises sitagliptin phosphate, a cation exchange resin, an impregnant, and a capsule material. The sitagliptin phosphate resin sustained-release microcapsule is obtained by performing static or dynamic drug loading of sitagliptin phosphate on the cation exchange resin to obtain a sitagliptin phosphate drug resin, then impregnating the resin with the impregnant to obtain an impregnated drug resin, and then coating the impregnated drug resin with the capsule material. The weight ratio of sitagliptin phosphate to the cation exchange resin is 1:4-9:4. The cation exchange resin is a sulfonic acid-type strongly acidic cation exchange resin. The capsule material is ammonium polymethacrylate or ethyl cellulose. The impregnant is polyethylene glycol. The sitagliptin phosphate resin sustained-release microcapsule of the present invention exhibits a release degree of about 75% at 10 h, indicating a significant sustained-release effect. The microcapsule can stabilize the plasma concentration level.

Description

Preparation method and application of sitagliptin phosphate resin sustained-release microcapsules Technical fields:

[0001] This invention belongs to the field of pharmaceutical technology and relates to a method for preparing sitagliptin phosphate resin sustained-release microcapsules (SP-DR-microcapsules) and their application. Background technology:

[0002] Diabetes mellitus (DM) is divided into type I and type II, characterized by chronic, persistent hyperglycemia. It can affect various parts of the body and, in severe cases, cause various complications, thus impacting human health. However, traditional DM treatments all have varying degrees of side effects, making the development of new formulations that can reduce these side effects an urgent priority.

[0003] Sitagliptin phosphate (SP) is a weakly acidic substance with a pKa of 7.7. Its chemical name is 7-[1-oxo-(3R)-3-amino-4-(2,4,5-trifluorophenyl)butyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-a]pyrazine phosphate monohydrate, and its molecular formula is C2. 16 H 15 F6N5O·H3PO4. SP is a white powder, readily soluble in water, with a pH-dependent solubility; the lower the pH, the higher the solubility of SP in water. It is slightly soluble in ethanol, acetone, and acetonitrile, and insoluble in isopropanol and isopropyl acetate. It has a melting point of 206.37℃ and good stability.

[0004] SP belongs to the DPP-4 inhibitor class of diabetes mellitus (DM) treatment drugs. It has shown significant clinical efficacy in treating type II DM, effectively enhancing patient function, lowering blood glucose levels, and regulating pancreatic islet cell secretion. Glucagon secreted by pancreatic alpha cells (raising blood glucose) and insulin secreted by pancreatic β cells (lowering blood glucose) are a pair of key hormones that antagonize each other, regulate blood glucose levels, and maintain stability. SP not only directly acts on active incretins, enabling their continuous secretion throughout the day and playing a crucial role in glucose metabolism, but also inhibits DPP-4, prolongs GLP-1 activity, increases GLP-1 levels, promotes insulin secretion, inhibits alpha cell glucagon secretion, and improves β cell function and promotes β cell regeneration to secrete insulin, thereby lowering the patient's blood glucose levels.

[0005] After oral administration, SP is absorbed through the gastrointestinal tract, leading to elevated blood drug concentrations and potentially causing mild to moderate adverse reactions, including upper respiratory tract infections, nasopharyngitis, headaches, and weight changes. Furthermore, the dosage needs to be adjusted frequently according to the patient's condition, causing considerable inconvenience. Solid oral formulations are also inconvenient for patients with swallowing difficulties.

[0006] Currently, the SP formulations available domestically and internationally are SP tablets manufactured by Merck, and there are no other dosage forms of SP products on the market domestically or internationally. This indicates that there are no sustained-release dosage forms of SP products available domestically or internationally.

[0007] Therefore, it is necessary to develop an SP preparation that can reduce adverse reactions of SP through sustained release, facilitate dosage adjustment, and be convenient for patients with swallowing difficulties to take—an SP liquid oral sustained-release preparation.

[0008] There are no existing reports on preparing sitagliptin phosphate into drug resin microcapsules and further preparing them into liquid sustained-release suspensions. Summary of the Invention:

[0009] To address the problems existing in the prior art, this invention provides sitagliptin phosphate resin sustained-release microcapsules, their preparation, and their applications.

[0010] This invention is achieved through the following technical solution:

[0011] The present invention first provides a sitagliptin phosphate resin sustained-release microcapsule, comprising sitagliptin phosphate, cation exchange resin (CER), impregnating agent, and capsule material;

[0012] The sitagliptin phosphate resin sustained-release microcapsules are obtained by statically or dynamically loading sitagliptin phosphate with a cation exchange resin to obtain sitagliptin phosphate drug resin, then impregnating it with an impregnating agent to obtain impregnated drug resin (SP-DR-impregnation), and finally coating it with a capsule material.

[0013] The weight ratio of sitagliptin phosphate to cation exchange resin is 1:4-9:4, preferably 3:4-9:4;

[0014] The cation exchange resin is a sulfonic acid type strong acid cation exchange resin, preferably a strong acid cation exchange resin 005×7 or 001×7 with a crosslinking degree of 7.

[0015] The cation exchange resin is pretreated to obtain sodium-form or hydrogen-form cation exchange resin;

[0016] The impregnating agent is an aqueous solution of polyethylene glycol (PEG), preferably an aqueous solution of PEG4000;

[0017] The mass concentration of the polyethylene glycol (PEG) aqueous solution is 10-15%;

[0018] The mass ratio of sitagliptin phosphate drug resin to impregnating agent is 1:2-3;

[0019] The capsule material comprises 1.0-2.5% of the mass of the drug-impregnated resin;

[0020] The encapsulation material is polyammonium methacrylate or ethyl cellulose, preferably polyammonium methacrylate I (Ureleas RL100), which is a water-insoluble polymer material and a sustained-release polymer material. It does not come into direct contact with the drug, but encapsulates the drug and swells in the release medium to release the drug slowly.

[0021] The above-mentioned method for preparing sitagliptin phosphate resin sustained-release microcapsules includes the following steps:

[0022] (1) Pretreatment of cation exchange resin;

[0023] (2) Preparation of sitagliptin phosphate drug resin (SP-DR) by static drug loading method:

[0024] Sitagliptin phosphate was dissolved in water in a reaction vessel, then cation exchange resin was added, and the mixture was stirred, filtered, washed, and dried to obtain sitagliptin phosphate drug resin.

[0025] (3) Preparation of drug-impregnating resin:

[0026] Sitagliptin phosphate drug resin is mixed and stirred with an impregnating agent to form an impregnated drug resin (SP-DR-impregnation);

[0027] (4) Dissolve the capsule material in an organic solvent and add the drug-impregnating resin. Stir to disperse the two evenly and form a suspension as the inner oil phase.

[0028] (5) A mixture of liquid paraffin and emulsifier is placed in a reaction vessel to form an outer oil phase;

[0029] (6) The inner oil phase is slowly added to the outer oil phase under stirring and stirred. After the solvent is completely evaporated, the reaction ends, the material is released, and the product is obtained by filtration, washing and drying with petroleum ether to obtain sitagliptin phosphate resin sustained-release microcapsules.

[0030] In step (1), the cation exchange resin pretreatment method is as follows:

[0031] After sieving and washing with water to remove impurities, CER (005×7) was soaked in ethanol overnight to remove any adsorbed organic matter, and then washed with water until no ethanol residue remained. The CER treated above was then soaked in 2-3 times its volume of 0.5 mol / L HCl solution for 2 hours with constant stirring, followed by washing with water until neutral (this is called "acid washing"). Next, the CER was soaked in 2-3 times its volume of 0.5 mol / L NaOH solution for 2 hours with constant stirring, followed by washing with water until neutral (this is called "alkali washing"). This process of alternating acid and alkali washing was repeated 2-3 times (the final wash should be alkali washing until neutral). Finally, the CER was dried in an electrically heated drying oven at 50°C. The final product was converted into sodium-form resin for later use.

[0032] In step (2), the particle size of the cation exchange resin is 100-250 mesh, preferably 100-150 mesh.

[0033] In step (2), the initial concentration of sitagliptin phosphate is 1-4 mg / mL, preferably 2-4 mg / mL.

[0034] In step (2), the weight ratio of sitagliptin phosphate to cation exchange resin is 1:4-9:4, preferably 3:4-9:4.

[0035] In step (2), the drug loading temperature is 25℃-45℃, preferably 35℃-40℃.

[0036] In step (3), the mass ratio of sitagliptin phosphate drug resin to impregnating agent is 1:2-3.

[0037] In step (4), the capsule material is Urelease RL100 and the organic solvent is anhydrous ethanol.

[0038] In step (5), the mass ratio of liquid paraffin: anhydrous ethanol: S-80 is 8:3-4:1-2, preferably 8:3:1.

[0039] In step (6), the stirring speed is 800-1200 RPM, the stirring time is 4-6 hours, and the temperature is 30-50℃.

[0040] Furthermore, the present invention provides a sitagliptin phosphate resin liquid sustained-release suspension comprising sitagliptin phosphate resin sustained-release microcapsules and a suspending agent, wherein the mass ratio of sitagliptin phosphate resin sustained-release microcapsules to the suspending agent is 4-6:1.

[0041] The preferred suspending agent is xanthan gum.

[0042] The sitagliptin phosphate drug resin microcapsules of the present invention can be further prepared into tablets, granules, dry suspensions or capsules with pharmaceutically acceptable carriers.

[0043] In this invention, the particle size of sitagliptin phosphate resin sustained-release microcapsules is less than 200 μm.

[0044] The sitagliptin phosphate of the present invention can also be replaced by easily soluble drugs or drugs with unpleasant tastes such as bitterness, sourness, astringency, or numbness.

[0045] Drug ion exchange resin sustained-release suspensions are an excellent choice because the ions on the groups in the ion exchange resin can exchange with drug ions of the same charge to form a drug ion exchange resin. SP, when dissolved in a solvent, forms SP cations, which can exchange with cations in CER in the solvent to form SP-DR. These are then impregnated and coated to prepare SP-DR microcapsules. Further, suspending agents and other excipients can be added to prepare a suspension. The preparation principle and process are simple. Due to this characteristic of SP and CER, SP-DR microcapsule suspensions have advantages over other SP liquid sustained-release oral dosage forms.

[0046] This invention utilizes ion exchange resin drug loading technology to prepare SP oral liquid sustained-release drug resin microcapsules, achieving a release rate of approximately 75% after 10 hours. This demonstrates a significant sustained-release effect, stabilizing blood drug concentrations, reducing the severity of adverse reactions, decreasing the frequency of medication administration, and facilitating dosage dispensing for patients with swallowing difficulties. This improves patient safety, and the product has a better taste than existing products, making it more acceptable to a wide range of patients, especially young children, the elderly, and those with swallowing disorders. The capsule material of this invention does not dissolve in the stomach, thus avoiding gastric irritation. The drug is a phosphate, easily absorbed in the stomach, and the core (drug resin) provides uniform coverage. The technical parameters used in this invention are stable and reliable, with good operational reproducibility, making it suitable for industrial-scale production. Furthermore, this preparation method overcomes the technical shortcomings of existing technologies, such as low recovery rates in fluidized beds and electrostatic adsorption. Attached image description:

[0047] Figure 1 shows the effect of cation exchange resin particle size on static drug loading (n=3);

[0048] Figure 2 shows the effect of initial drug concentration on static drug loading;

[0049] Figure 3 shows the effect of the drug-to-cation exchange resin weight ratio on static drug loading.

[0050] Figure 4 shows the effect of different drug loading temperatures on static drug loading (n=3);

[0051] Figure 5 shows the effect of rotational speed on the in vitro release behavior of sitagliptin phosphate resin (n=3);

[0052] Figure 6 shows the effect of temperature on the in vitro release behavior of sitagliptin phosphate resin (n=3);

[0053] Figure 7 shows the effect of ion concentration on the in vitro release behavior of sitagliptin phosphate resin (n=3);

[0054] Figure 8 shows electron microscope (A1-D1) images and magnified electron microscope (A2-D2) images of sitagliptin phosphate (SP), B1: cation exchange resin (CER), C1: physical mixture of sitagliptin phosphate and cation exchange resin (SP+CER), and D1: sitagliptin phosphate drug resin.

[0055] Figure 9 shows the X-ray diffraction (XRD) powder diffraction pattern of A: sitagliptin phosphate (SP), B: cation exchange resin (CER), C: physical mixture of sitagliptin phosphate and cation exchange resin (SP-CER), and D: sitagliptin phosphate drug resin (SP-DR).

[0056] Figure 10 shows the Fourier transform infrared absorption spectrum (FTIR) of A: sitagliptin phosphate (SP), B: cation exchange resin (CER), C: physical mixture of sitagliptin phosphate and cation exchange resin (SP-CER), and D: sitagliptin phosphate drug resin (SP-DR).

[0057] Figure 11 shows the in vitro release behavior of sitagliptin phosphate drug resin (SP-DR) in 0.15 mol / L NaCl solution after impregnation;

[0058] Figure 12 is a three-phase diagram of liquid paraffin / anhydrous ethanol / Span-80 (S-80) (room temperature, atmospheric pressure);

[0059] Figure 13 is a process flow diagram of emulsified solvent coating;

[0060] Figure 14 shows the effect of coating stirring (curing) temperature on the in vitro release behavior of sitagliptin phosphate resin (SP-DR) sustained-release microcapsules (n=3);

[0061] Figure 15 shows the effect of coating stirring (curing) time on the in vitro release behavior of sitagliptin phosphate resin (SP-DR) sustained-release microcapsules (n=3);

[0062] Figure 16 shows the effect of coating stirring speed on the in vitro release behavior of sitagliptin phosphate resin (SP-DR) sustained-release microcapsules (n=3);

[0063] Figure 17 shows the effect of the mass percentage of Urelease RL100 coating material in sitagliptin phosphate drug resin (SP-DR) impregnation on the in vitro release of sitagliptin phosphate resin (SP-DR) sustained-release microcapsules (n=3);

[0064] Figure 18 shows the release reproducibility of three batches of sitagliptin phosphate resin (SP-DR) sustained-release microcapsules (n=3);

[0065] Figure 19 shows the scanning electron microscope (SEM) image and a magnified version of the SEM image;

[0066] E1, E2: Sitagliptin phosphate drug resin (SP-DR) impregnated with F1, F2: Sitagliptin phosphate resin (SP-DR) sustained-release microcapsules. Detailed Implementation

[0067] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0068] Example 1: Solubility of sitagliptin phosphate

[0069] Determination of solubility:

[0070] Sitagliptin phosphate was supersaturated in deionized water, 0.15 mol / L NaCl, and 0.5 mol / L NaCl under a 37°C water bath. The solutions were then filtered through 0.45 μm microporous membranes, and the filtrates were collected and their UV absorbance was measured.

[0071] Table 1. Solubility of sitagliptin phosphate in water, 0.15 mol / L NaCl solution, and 0.5 mol / L NaCl solution (n = 3)

[0072] Example 2 Determination of the stability of sitagliptin phosphate (SP) solution

[0073] Take an appropriate amount of sitagliptin phosphate and dissolve it in water, 0.15 mol / L NaCl, and 0.5 mol / L NaCl to prepare SP aqueous solutions of low, medium, and high concentrations (10 μg / mL, 40 μg / mL, and 160 μg / mL). Incubate at room temperature and take samples at 0 h, 2 h, 4 h, 8 h, 10 h, 12 h, and 24 h. Measure the UV absorbance at the wavelength required for sitagliptin phosphate determination. Calculate the sitagliptin phosphate concentration using MS Excel software to investigate the drug's stability in aqueous solutions. Determine the stability of sitagliptin phosphate in 0.15 mol / L NaCl and 0.5 mol / L NaCl solutions using the same method.

[0074] The results are shown in Table 2. The RSD values ​​of sitagliptin phosphate in water, 0.15 mol / L NaCl, and 0.5 mol / L NaCl solutions were all less than 5% within 24 h, indicating good stability.

[0075] Table 2. Stability test results of sitagliptin phosphate in water, 0.15 mol / L NaCl, and 0.5 mol / L NaCl solutions.

[0076] Example 3 Preparation of sitagliptin phosphate drug resin (SP-DR)

[0077] Pretreatment of cation exchange resin (CER): After sieving and washing with water to remove impurities, CER (005×7) was soaked in ethanol overnight to remove adsorbed organic matter, and then washed with water until no ethanol residue remained. The CER treated above was then soaked in 2-3 times its volume of 0.5 mol / L HCl solution for 2 hours with continuous stirring, followed by washing with water until neutral (this is called "acid washing"). Next, the CER was soaked in 2-3 times its volume of 0.5 mol / L NaOH solution for 2 hours with continuous stirring, followed by washing with water until neutral (this is called "alkali washing"). This process of alternating acid and alkali washing was repeated 2-3 times (the final wash should be alkali washing until neutral). Finally, the CER was dried in an electrically heated drying oven at 50°C. This experiment ultimately transformed the resin into a sodium-form resin for later use.

[0078] The cation exchange resins used in the static drug loading method described below are all pretreated sodium-type CER resins.

[0079] Preparation of SP-DR by static drug loading method: A certain amount of SP was weighed and dissolved in an appropriate volume of deionized water, stirred for a period of time, and then a certain amount of CER was gradually added to the water. The mass ratio of SP to CER was 3:4. Static drug loading was carried out at a controlled temperature of 35℃. Properties of SP-DR:

[0080] (1) Drug loading capacity determination:

[0081] After drug loading equilibrium is achieved, the sample is filtered, washed, and dried for later use. The drug loading (Quantity of drug loading, Q) of the CER is calculated according to formulas (1), (2), and (3). t (Efficiency of drug loading, E) and Degree of drug loading, D.

[0082] Q t (%) represents the drug loading at time t; V (mL) represents the solution volume; C0 (mg / mL) represents the initial drug concentration; C t Let W be the drug concentration at time t; r (mg) represents the mass of CER; Q ∞ (%) represents the drug loading of the CER at equilibrium.

[0083] (2) Dissolution test

[0084] Dissolution medium: 0.15 mol / L NaCl solution, which has the closest ionic strength to the normal physiological conditions of the human body, was selected as the dissolution medium for SP-DR sustained-release microcapsules.

[0085] Dissolution method: The shaking speed was set to 100 RPM, and 0.15 mol / L NaCl solution was used as the dissolution medium with a volume of 100 mL and a temperature of 37℃.

[0086] Accurately weigh each sample (equivalent to 10 mg sitagliptin phosphate) and place it in an Erlenmeyer flask containing 100 mL of dissolution medium. Take 1 mL of sample at the set time, dilute to a certain factor, filter through a 0.45 μm microporous membrane, and determine the cumulative drug release by ultraviolet spectrophotometry. Perform the experiment in triplicate. Calculate the cumulative release rate using MS Excel software, and generate curves and error bars using GraphPad Prism 9.5.1 (733).

[0087] This invention employs the similarity factor method, recommended in the United States, to evaluate differences in drug release behavior of pharmaceutical resins. The similarity factor, transformed by the squared error and its reciprocal square root, is used to examine the similarity between two curves. This allows for direct statistical analysis of release data without the need to fit various release rates and avoids spurious conclusions arising from intuitive analysis. Its basic equation is as follows:

[0088] Rt and Tt represent the cumulative release rate of sitagliptin phosphate resin at sampling time t under different experimental conditions, and n represents the total number of samplings. The larger f2 is, the higher the goodness of fit. When f2 ≥ 50, it indicates that the release behavior of the two is similar.

[0089] Example 4: Effect of resin particle size on static drug loading

[0090] 9g of sitagliptin phosphate was placed in a reaction vessel, 4.5L of distilled water was added, and the mixture was stirred to dissolve. Then, 16g of cation exchange resin (CER) was added, and static adsorption was performed at 35℃. After stirring, filtration, washing, and drying, sitagliptin phosphate drug resin was obtained. The particle sizes of the cation exchange resin were 100-150 mesh, 150-200 mesh, and 200-250 mesh, respectively. The drug loading of the prepared sitagliptin phosphate drug resin is shown in Figure 1.

[0091] As the particle size of the cation exchange resin (CER) decreases, the exchange rate of sitagliptin phosphate with ions in the CER and the drug loading increase accordingly. However, this trend becomes less pronounced when the particle size decreases to a certain extent. Therefore, the particle size of the cation exchange resin in this invention is 100–250 mesh. To facilitate subsequent solid-liquid separation, the CER particle size in the static drug loading formulation is determined to be 100–150 mesh.

[0092] Example 5: Effect of initial drug concentration on static drug loading

[0093] The initial drug concentration was changed, and the CER particle size was set to 100–150 mesh, while other conditions remained the same as in Example 4. The drug loading of the prepared sitagliptin phosphate resin is shown in Figure 2.

[0094] The results showed that the ion exchange rate and drug loading capacity between SP and CER remained essentially unchanged with increasing initial SP concentration. Therefore, the initial SP concentration was 1-4 mg / mL, preferably 2-4 mg / mL. To ensure an appropriate SP solution volume during static drug loading, the initial SP concentration in the static drug loading formulation was determined to be 2 mg / mL.

[0095] Example 6: Effect of SP to CER weight ratio on static drug loading

[0096] The weight ratio of SP to CER was adjusted, and the CER particle size was 100-150 mesh. Other conditions were the same as in Example 4. The weight ratios of SP to CER were 1:4, 3:4, 5:4, 7:4, and 9:4. The drug loading and drug loading efficiency of the prepared sitagliptin phosphate drug resin are shown in Figure 3 and Table 3.

[0097] Table 3 Effect of SP:CER weight ratio on static drug loading

[0098] When the SP:CER weight ratio is 1:4-9:4, drug utilization decreases while drug loading increases with the increase of the SP ratio. When the SP:CER weight ratio is 3:4-9:4, both drug utilization and drug loading are above 50%. To save costs in the static drug loading process and maintain high drug utilization and a relatively balanced drug loading, the SP:CER weight ratio was determined to be 3:4.

[0099] Example 7: Effect of drug loading temperature on static drug loading

[0100] The drug loading temperature was changed to 25℃, 30℃, 35℃, 40℃ and 45℃, and the CER particle size was 100-150 mesh. Other conditions were the same as in Example 4. The changes in drug loading degree were investigated. The results are shown in Figure 4.

[0101] The results showed that the drug loading rate increased with increasing drug loading temperature during the SP-CER exchange process. To ensure a faster drug loading exchange rate and to allow the shaker to reach the drug loading temperature in a shorter time, the drug loading temperature in the static drug loading formulation was determined to be 35-40℃.

[0102] Example 8 Preparation of sitagliptin phosphate drug resin

[0103] 9g of sitagliptin phosphate was placed in a reaction vessel, 4.5L of distilled water was added, and the mixture was stirred to dissolve. Then, 16g of cation exchange resin CER was added, and static adsorption was performed at 35℃. After stirring, filtration, washing, and drying, sitagliptin phosphate drug resin was obtained. The particle size of the cation exchange resin was 100-150 mesh.

[0104] Example 9 Static exchange kinetics study of sitagliptin phosphate drug resin (SP-DR)

[0105] Data fitting was performed on the static drug loading kinetics of Example 8, and the results are shown in Table 4. The results indicate that the kinetics of SP-DR prepared by the static method fits the first-order model best (R0). 2 =0.9894), the second-order model fit is slightly worse (R = 0.9894). 2 =0.9891), the zero-order model has the worst fit (R² = 0.9891). 2 =0.9256). In summary, the preparation of SP-DR is a first-order kinetic process, and the fitting equation is ln(1-D) = -0.0139t (35℃).

[0106] 1-D=k0t+a Zero-order model

[0107] ln(1-D)=k1t First-order model

[0108] 1 / (1-D)=k2t+b second-order model

[0109] Table 4. Kinetic fitting of drug loading curves (35℃)

[0110] Table 5 Rate constants and equilibrium exchange rates (at different temperatures) (n=3)

[0111] As shown in Table 5, under the condition that other parameters remain unchanged, the rate constant k1 increases with increasing temperature (from 0.0074 min). -1 ~0.0349min -1 ), Q ∞ The increase indicates that higher temperature favors the ion exchange reaction between SP and CER and increases Q. ∞ The activation energy Ea of drug loading can be obtained by regressing lnk1 against 1 / T at 298K, 303K, 308K, 313K, and 318K. Simultaneously, according to the Arrehetius formula, the fitted equation is lnk1 = -Ea / RT + A = -7049.2 / T + 18.683(R). 2 =0.9716), therefore Ea = 58.61 kJ·mol -1 .

[0112] Example 10 Static exchange thermodynamics study of sitagliptin phosphate drug resin (SP-DR)

[0113] Static exchange thermodynamics was studied on the process of preparing sitagliptin phosphate drug resin in Example 8.

[0114] The interaction between SP and DR is achieved through the reaction of SP ions in the solution with Na+ on the CER. + Drug loading is achieved through ion exchange. The reaction process is as follows:

[0115] R - Na + +D + →R - D + +Na +

[0116] In the reaction formula, R - Na + Represents strongly acidic CER, D + This represents SP ions in a free state in the solution, Na + It is an exchangeable ion on the strongly acidic CER structure. The apparent equilibrium constant Ke is calculated using the following basic equation:

[0117] In the formula, [D + ] r The molar concentration of SP in CER (mmol·g) -1 ), [Na + ] s Na in solution + molar concentration (mmol·L) - 1 ), [D + ] s The molar concentration of SP in the solution (mmol·L) -1 ), [Na + ] r Na in CER + molar concentration (mmol·g) - 1 ).

[0118] Ke reflects the strength of the binding ability between CER and SP. The larger the Ke, the easier it is for SP to undergo an ion exchange reaction with CER to eventually form SP-DR. The apparent equilibrium constant Ke for the binding of SP and CER at different temperatures was calculated. The results are shown in Table 6. As shown in Table 6, Ke increases with increasing temperature, indicating that increasing temperature is beneficial for the preparation of SP drug-loaded resin.

[0119] Table 6. Equilibrium constant K at different temperatures e (n=3)

[0120] Free energy change ΔG during SP-DR preparation process θ r, m, heat of reaction ΔH θ r, m, and entropy value ΔS θ r and m can be obtained by fitting the following formulas respectively:

[0121] ΔG θ r，m =-RT ln K e

[0122] ΔG θ r,m =ΔH θ r,m -TΔS θ r,m

[0123] Where R = 8.314 J·K -1 ·mol -1 Free energy change ΔG θ r,m, heat of reaction ΔH θ r, m, and entropy value ΔS θ The calculated results for r and m are shown in Table 7. Table 7 shows that the preparation reaction of SP-DR at different temperatures is ΔG. θ r,m <0, △S θ r,m A value >0 indicates that when CER reacts with SP, its free energy decreases, its entropy increases, and the ion exchange reaction proceeds spontaneously to the right. The heat of exchange reaction is ΔH. θ r,m A value >0 indicates that the ion exchange reaction is an endothermic process, so increasing the temperature is beneficial for the reaction to proceed.

[0124] Table 7 ΔG of SP at various temperatures θ r,m , △H θ r,m , △S θ r,m

[0125] Example 11 Determination of dissolution conditions for sitagliptin phosphate drug resin (SP-DR)

[0126] (1) Effect of dissolution medium volume on drug release

[0127] Following the dissolution method in Example 3, the mass-to-volume ratio of SP-DR to dissolution medium was changed to 1:4, 1:2, and 1:1. The results showed that as the mass of the dissolution medium increased, its volume also increased, leading to a higher in vitro release rate and cumulative release rate of the drug in SP-DR, with near-complete release at 240 min. Table 8 shows that f2 ≥ 50. In summary, all three mass-to-volume ratios (SP-DR: dissolution medium) met the leakage conditions and had virtually no impact on the release behavior. To maximize the satisfaction of the leakage conditions, the mass-to-volume ratio (SP-DR: dissolution medium) in the SP-DR dissolution conditions was determined to be 1:4.

[0128] Table 8. Similarity analysis of the effect of media volume on the in vitro release behavior of SP-DR

[0129] (2) Effect of rotation speed on in vitro drug release behavior

[0130] Following the dissolution method in Example 3, the rotation speeds were changed to 50 RPM, 100 RPM, and 150 RPM, and the results are shown in Figure 5. As the rotation speed increased, the in vitro release rate and cumulative release rate of the drug in SP-DR also increased, and the drug was essentially completely released after 240 min. Table 9 shows that when the rotation speed increased from 50 RPM to above 100 RPM, f2 < 50, indicating that the release behaviors were dissimilar and the rotation speed had a significant impact on the release. When the rotation speed increased from 100 RPM to 150 RPM, f2 = 79, indicating that the release behaviors were similar and the rotation speed had a relatively small impact on the release. Since the dissolution medium surface was very stable at a shaker speed of 50 RPM, to simulate gastrointestinal peristalsis as much as possible, the shaker rotation speed for SP-DR dissolution was determined to be 100 RPM.

[0131] Table 9. Similarity analysis of the effect of rotational speed on the in vitro release behavior of SP-DR

[0132] (3) Effect of temperature on the in vitro release behavior of sitagliptin phosphate drug resin (SP-DR)

[0133] Following the dissolution method in Example 3, the temperatures were changed to 25℃, 37℃, and 50℃, and the results are shown in Figure 6. As the temperature increased, the in vitro release rate and cumulative release rate of the drug in SP-DR also increased, and the drug was essentially completely released after 240 minutes. Table 10 shows that when the temperature difference is small, f2 ≥ 50, indicating similar release behavior and relatively small influence of temperature on release. When the temperature increases from 25℃ to 50℃, f2 = 37, indicating dissimilar release behavior and a significant influence of rotation speed on release. Since the normal physiological body temperature is around 37℃, the temperature for the SP-DR dissolution conditions was determined to be 37℃ to simulate normal human physiological body temperature.

[0134] Table 10. Similarity analysis of the effect of release temperature on the in vitro release behavior of SP-DR

[0135] (4) Effect of mediator ion concentration on in vitro release behavior of sitagliptin phosphate drug resin (SP-DR)

[0136] Following the dissolution method in Example 3, the ion concentrations of the medium were changed to 0.15 mol / L NaCl and 0.5 mol / L NaCl, and the results are shown in Figure 7. As the ion concentration of the medium increased, the in vitro release rate and cumulative release rate of the drug in SP-DR also increased, and the release was essentially complete at 240 min. Table 11 shows that f2 = 63, indicating similar release behavior and that the ion concentration of the medium had virtually no effect on the release. Since physiological saline is isotonic with human tissue fluid, to simulate the ion concentration and types in the human body, the dissolution medium in the SP-DR dissolution conditions was determined to be a 0.15 mol / L NaCl solution.

[0137] Table 11 Similarity analysis of the effect of ion concentration on the in vitro release behavior of SP-DR

[0138] Example 12 Characterization of Sitagliptin Phosphate (SP), Cation Exchange Resin (CER), Sitagliptin Phosphate-Cation Exchange Resin Physical Mixture (SP+CER), and Sitagliptin Phosphate Drug Resin (SP-DR)

[0139] (1) SEM morphological analysis

[0140] The SEM results are shown in Figure 8. SP (Figure 8A1-A2) are prismatic; CER (Figure 8B1-B2) are smooth spherical; compared with SP-DR (Figure 8D1-D2), no SP drug particles were observed on the surface of SP+CER (Figure 8C1-C2).

[0141] (2) XRD results

[0142] XRD analysis results are shown in Figure 9. SP has a series of obvious crystal diffraction peaks (Figure 9A); CER is an amorphous polymer and no crystal peaks were observed (Figure 9B); SP+CER shows a superposition of drug crystal peaks and CER amorphous diffusion peaks (Figure 9C); while SP-DR has no crystal diffraction peaks (Figure 9D).

[0143] (3) FTIR results,

[0144] FTIR measurements were performed, and the results are shown in Figure 10. The characteristic absorption peak of SP (Figure 10A) is at 3413 cm⁻¹. -1 υ(NH), 3061cm -1 Aromatic ring υ(CH), 2922cm -1 υ(CH) is a saturated carbon-hydrogen bond, 1672 cm⁻¹ -1 Carbonyl group υ (C=O), 1557 cm -1 The peak for the aromatic ring skeleton vibration is υ (C=C); the characteristic absorption peaks of CER (Figure 10B) are: 3455 cm⁻¹ -1 υ(OH) is a hydroxyl group, 2925 cm -1 υ(CH), 1637cm -1 The peak υ (C=C) represents the aromatic ring skeleton vibration. A significant difference between SP-DR (Fig. 10D) and SP+CER (Fig. 10C) is that the peak υ is at 3413 cm⁻¹. -1 The vibrational peak of υ(NH) disappears.

[0145] Example 13

[0146] At 60°C, an aqueous solution of PEG 4000 (mass fraction of 10-15%) was mixed and stirred with SP-DR (Example 8) for 30 min, then filtered and dried at 50°C for 10 min in an electric heating drying oven to obtain SP-DR-impregnation. The mass ratio of PEG4000 to SP-DR was 2-3:1.

[0147] The results of the in vitro dissolution experiment are shown in Figure 11. The results show that the SP-DR-impregnated drug was basically completely released after 10 hours, but failed to achieve a good sustained-release effect. Therefore, further coating of SP-DR-impregnation was carried out to control the release and achieve the ideal sustained-release effect.

[0148] Example 14 Selection of emulsion system in emulsion solvent evaporation coating

[0149] At room temperature and normal pressure, a series of liquid paraffin and S-80 mixtures with different proportions were prepared. Ethanol was added dropwise to each mixture, and the mixture was stirred. The changes in the system (clarity → turbidity → separation) were observed. The amount of ethanol added at the initial turbidity point and the separation point was recorded. The mass percentage of each component was calculated. A ternary phase diagram of liquid paraffin / ethanol / S-80 was plotted using Origin. A suitable mass ratio of liquid paraffin: anhydrous ethanol: S-80 was selected in the middle of the emulsion zone. The results are shown in Figure 12. The mass ratio of liquid paraffin: anhydrous ethanol: S-80 is 8:3:1.

[0150] Example 15 Preparation of SP-DR-microcapsules by emulsification solvent evaporation method

[0151] First, the encapsulation material is dissolved in an organic solvent to form a coating solution, which is then mixed with SP-DR impregnation to form a dispersed phase. Next, surfactant S-80 and liquid paraffin are stirred and mixed to form a continuous phase. Finally, the dispersed phase is stirred and added to the continuous phase to form an emulsion.

[0152] The organic solvent must be volatile and immiscible with the continuous phase but have a certain degree of solubility, so that it can be evaporated from the emulsion system by heating. After the organic solvent has completely evaporated, the system becomes clear and the emulsion system no longer exists. The clear system is washed with petroleum ether, filtered, and dried to obtain SP-DR-microcapsules.

[0153] Through initial screening, the capsule material was determined to be Urelease RL100, and the organic solvent was determined to be anhydrous ethanol.

[0154] Example 16 Effect of curing temperature (i.e., stirring temperature) during coating on the in vitro release behavior of SP-DR microcapsules

[0155] First, Urelease RL100 is dissolved in anhydrous ethanol to form a coating solution, then mixed with SP-DR to form a dispersed phase. Next, S-80 and liquid paraffin are stirred and mixed to form a continuous phase. Finally, the dispersed phase is stirred and added to the continuous phase to form an emulsion.

[0156] The mass ratio of liquid paraffin:ethanol:S-80 was 8:3:1; Urelease RL100 accounted for 2.5% of the SP-DR-impregnation mass; the curing temperatures were 30℃, 50℃, and 70℃; the curing time was 4h; the coating stirring speed was 1200RPM; and the concentration of SP-DR-impregnation was 10%.

[0157] The changes in the in vitro release rate and cumulative release amount of the drug are shown in Figure 14.

[0158] The results showed that the in vitro release rate and cumulative release rate of the drug in SP-DR microcapsules increased with increasing curing temperature. Table 12 shows that when the temperature decreased from 50℃ to 30℃, f2 ≥ 50, indicating similar release behavior and minimal effect of curing temperature on release. When the temperature decreased from 70℃ to below 50℃, f2 < 50, indicating dissimilar release behavior and significant impact of curing temperature on release. At higher temperatures, anhydrous ethanol evaporated more quickly, resulting in a looser coating film and a faster drug release rate. At lower curing temperatures, the evaporation rate of anhydrous ethanol was slower, resulting in a denser coating film and a slower drug release rate. Therefore, only under suitable temperature conditions can a uniform and dense coating film be formed, achieving a better drug release effect. The optimal curing temperature during the coating process was determined to be 30-50℃, with 50℃ being the best.

[0159] Table 12 Similarity analysis of the effect of curing temperature on the in vitro release behavior of SP-DR microcapsules

[0160] Example 17 Effect of curing time (i.e., stirring time) on the in vitro release behavior of SP-DR microcapsules

[0161] Following the method of Example 16, with a curing temperature of 50°C, the curing time was changed to 4h, 6h, and 8h, and the changes in the in vitro release rate and cumulative release amount of the drug are shown in Figure 15.

[0162] The results showed that the in vitro release rate and cumulative release rate of the drug in SP-DR microcapsules decreased with increasing curing time. Table 13 shows that when the curing times were similar, f2 ≥ 50, indicating similar release behavior and minimal impact of curing time on release. However, when the curing time increased from 4h to 8h, f2 = 43, indicating dissimilar release behavior and a significant impact of curing time on release. When the curing time was short, the anhydrous ethanol had not completely evaporated, and the residual anhydrous ethanol, after being dried in an oven, formed pores on the microcapsules, resulting in a loose coating film and a faster drug release rate. Conversely, when the curing time was too long, the final coating film became too dense, slowing down the drug release rate. Therefore, only under moderate curing time conditions could a uniform and dense coating film be formed, achieving a better drug release effect. The optimal curing time during the coating process was determined to be 4-6h, with 4h being the best.

[0163] Table 13 Similarity analysis of the effect of curing time on the in vitro release behavior of SP-DR microcapsules

[0164] Example 18 Effect of Coating Stirring Rate on In Vitro Release Behavior of SP-DR-Microcapsules

[0165] Following the method of Example 16, with a curing temperature of 50°C and a curing time of 4 hours, the coating stirring speed was changed to 400 RPM, 800 RPM, and 1200 RPM. The changes in the in vitro release rate and cumulative release amount of the drug are shown in Figure 16.

[0166] The results showed that the in vitro release rate and cumulative release rate of the drug in SP-DR microcapsules increased with increasing coating stirring speed. Table 14 shows that when the coating stirring speeds were similar, f2 ≥ 50, indicating similar release behavior and minimal impact of coating stirring speed on release. However, when the coating stirring speed increased from 400 RPM to 1200 RPM, f2 = 44, indicating dissimilar release behavior and a significant impact of coating stirring speed on release. Excessive stirring speed led to rapid evaporation of anhydrous ethanol, resulting in poor film density and increased risk of emulsion splashing during preparation. Conversely, excessively slow stirring speeds prevented the formation of stable eddies, resulting in uneven dispersion of drug resin particles in the liquid phase. A significant portion of the resin settled and adhered to the bottom of the container, leading to significant microcapsule adhesion, uneven particle size distribution, and irregular drug release. Therefore, only under suitable coating stirring speed conditions can a uniform and dense coating film be formed, achieving a better drug release effect. The final determined coating stirring speed was 800-1200 RPM, with 800 RPM being the optimal value.

[0167] Table 14 Similarity analysis of the effect of coating stirring speed on the in vitro release behavior of SP-DR-microcapsules

[0168] Example 19 Effect of the mass percentage of Urelease RL100 in sitagliptin phosphate drug resin (SP-DR) impregnation on the in vitro release behavior of SP-DR microcapsules

[0169] Following the method of Example 16, with a curing temperature of 50°C, a curing time of 4 hours, and a coating stirring speed of 800 RPM, the mass percentage of Urelease RL100 in the SP-DR-impregnation was changed to 0%, 2.5%, and 5%, respectively. The changes in the in vitro drug release rate and cumulative release amount are shown in Figure 17.

[0170] The results showed that as the mass percentage of Urelease RL100 in the SP-DR-impregnation increased, the in vitro release rate and cumulative release rate of the drug in the SP-DR-microcapsules decreased accordingly. Furthermore, when the specific gravity of Urelease RL100 increased to 5%, the in vitro release rate significantly decreased (P < 0.05, n = 3). Table 15 shows that f2 < 50, indicating dissimilar release behaviors, and the mass percentage of Urelease RL100 in the SP-DR-impregnation had a significant impact on release. Since the viscosity of the coating solution increased with the increase of the mass percentage of Urelease RL100 in the SP-DR-impregnation, microcapsule adhesion occurred. Therefore, only under suitable mass percentage conditions of Urelease RL100 in the SP-DR-impregnation could a uniform and non-adhesive coating film be formed, achieving a better drug release effect. Finally, the mass percentage of Urelease RL100 in the SP-DR-impregnation during the coating process was determined to be 1.0-2.5%, preferably 2.5%.

[0171] Table 15. Similarity analysis of the effect of the mass percentage of Urelease RL100 in SP-DR-impregnation on the in vitro release behavior of SP-DR-microcapsules.

[0172] Example 20 Screening of target formulations for sitagliptin phosphate drug resin (SP-DR) microcapsules

[0173] Referring to Examples 14-19, various factors in the SP-DR-impregnation coating process were adjusted to prepare SP-DR-microcapsules, and in vitro dissolution experiments were conducted to calculate the average cumulative release over 10 hours. The results are shown in Table 16. The selection criterion for the target formulation was "the average cumulative release of SP-DR-microcapsules over 10 hours reaches about 75%". Formulations ②, ③, ④, and ⑦ can basically meet this standard. However, among these four formulations, the coating stirring speed of formulation ⑦ is relatively high, which easily causes liquid splashing during the coating stirring process and affects the coating effect. The temperature of formulation 3 is too high. Therefore, after comprehensive analysis, formulation ② was selected as the target formulation for preparing SP-DR-microcapsules.

[0174] Table 16 Screening of Coating Prescriptions (n=3)

[0175] Example 21 Preparation of sitagliptin phosphate drug resin (SP-DR) microcapsules

[0176] Three batches of SP-DR-microcapsules were prepared according to Formulation 2 in Example 20, and their release curves are shown in Figure 18. The release rates and equilibrium release amounts of the three batches of samples were basically the same, and the release was around 75% at 10 hours, showing good reproducibility.

[0177] The characterization results of SP-DR-impregnation and SP-DR-microcapsules are shown in Figure 19. The results indicate that both the impregnated membrane and the coating membrane were intact.

[0178] Example 22 Preparation of Sitagliptin Phosphate Drug Resin Liquid Sustained-Release Suspension

[0179] Take an appropriate amount of xanthan gum, a suspending agent, and add it to deionized water to dissolve or disperse it evenly. The mass fraction of xanthan gum is 0.3%-0.4%. Stir evenly, add SP-DR-microcapsules, and disperse evenly. The mass ratio of SP-DR-microcapsules to suspending agent is 5.25:1.

[0180] The sedimentation volume ratio refers to the ratio of the volume of sediment after a suspension has been left for a period of time to the original volume of the suspending agent. To ensure the stability of the system, the sedimentation volume ratio should generally be greater than 0.9. The prepared sustained-release suspension (100 mg SP-DR microcapsules mixed with 4 mL of suspending agent) was placed in a 5 mL stoppered graduated cylinder, and the height of the suspension (Height0, H0) was recorded. After standing at room temperature for 3 hours, the final height of the sediment (Height, H) was recorded, and the sedimentation volume ratio was calculated.

[0181] Redispersibility: After the prepared suspension (100 mg SP-DR microcapsules mixed with 4 mL suspending agent) was left to stand for a period of time, it was centrifuged and then inverted and shaken to achieve uniform dispersion again. The number of times it was shaken was recorded.

[0182] When the mass fraction of xanthan gum is 0.3%, the sedimentation volume ratio is 0.94 and the redispersibility of the suspension is 1; when the mass fraction of xanthan gum is 0.4%, the sedimentation volume ratio is 0.98 and the redispersibility is 1.

[0183] Example 23 Preparation of sitagliptin phosphate drug resin liquid sustained-release suspension (SP-DR-microcapsule-suspension)

[0184] Take an appropriate amount of xanthan gum, a suspending agent, and add it to deionized water to dissolve or disperse it evenly. Add an appropriate amount of wetting agent, flavoring agent, filler, and preservative, stir evenly, and add the prescribed amount of SP-DR-microcapsules to disperse evenly. The prescription of SP-DR-microcapsule-suspension is shown in Table 17.

[0185] Table 17 Formulation of SP-DR Microcapsule Suspension

Claims

1. Sitagliptin phosphate resin sustained-release microcapsules, characterized in that, The product comprises sitagliptin phosphate, cation exchange resin, impregnating agent, and capsule material. The weight ratio of sitagliptin phosphate to cation exchange resin is 1:4-9:4, preferably 3:4-9:

4. The mass ratio of sitagliptin phosphate drug resin to impregnating agent is 1:2-3. The sitagliptin phosphate drug resin microcapsules are obtained by static or dynamic drug loading of sitagliptin phosphate and cation exchange resin, followed by impregnation with impregnating agent to obtain impregnated drug resin, and then coating with capsule material.

2. The sitagliptin phosphate resin sustained-release microcapsules according to claim 1, characterized in that, The encapsulation material is polyammonium methacrylate or ethyl cellulose, preferably polyammonium methacrylate I, and the encapsulation material accounts for 1.0-2.5% of the mass percentage of the impregnated drug resin.

3. The sitagliptin phosphate resin sustained-release microcapsules according to claim 1 or 2, characterized in that, The cation exchange resin is a sulfonic acid type strong acid cation exchange resin, preferably a strong acid cation exchange resin 005×7 or 001×7 with a crosslinking degree of 7.

4. The sitagliptin phosphate resin sustained-release microcapsules according to claim 1 or 2, characterized in that, The impregnating agent is an aqueous solution of polyethylene glycol, preferably an aqueous solution of PEG 4000.

5. The method for preparing sitagliptin phosphate resin sustained-release microcapsules according to claim 1 or 2, characterized in that, Includes the following steps: (1) Pretreatment of cation exchange resin; Cation exchange resins are pretreated to obtain sodium-form or hydrogen-form cation exchange resins; (2) Preparation of sitagliptin phosphate drug resin by static drug loading method: Sitagliptin phosphate was dissolved in water in a reaction vessel, and then the cation exchange resin described in claim 3 was added. After stirring, filtration, washing, and drying, sitagliptin phosphate drug resin was obtained. (3) Preparation of drug-impregnating resin: Sitagliptin phosphate drug resin is mixed and stirred with an impregnating agent to form an impregnating drug resin; (4) Dissolve the capsule material in an organic solvent and add the drug-impregnating resin. Stir to disperse the two evenly and form a suspension as the inner oil phase. (5) A mixture of liquid paraffin and emulsifier is placed in a reaction vessel to form an outer oil phase; (6) The inner oil phase is slowly added to the outer oil phase under stirring and stirred. After the solvent is completely evaporated, the reaction ends, the material is released, and after filtration, washing and drying with petroleum ether, sitagliptin phosphate drug resin microcapsules are obtained.

6. The preparation method according to claim 5, characterized in that, In step (2), the particle size of the cation exchange resin is 100-250 mesh, preferably 100-150 mesh; the initial concentration of sitagliptin phosphate is 1-4 mg / mL, preferably 2-4 mg / mL; and the drug loading temperature is 25℃-45℃, preferably 35℃-40℃.

7. The preparation method according to claim 5, characterized in that, In step (4), the capsule material is polyammonium methacrylate and the organic solvent is anhydrous ethanol; in step (5), the mass ratio of liquid paraffin: anhydrous ethanol: Span-80 is 8:3-4:1-2, preferably 8:3:

1.

8. The preparation method according to claim 5, characterized in that, In step (6), the stirring speed is 800-1200 RPM, the curing time is 4-6 hours, and the curing temperature is 30-50℃.

9. Sitagliptin phosphate drug resin liquid sustained-release suspension, characterized in that, It comprises sitagliptin phosphate resin sustained-release microcapsules and a suspending agent as described in any one of claims 1-4.

10. The sitagliptin phosphate drug resin liquid sustained-release suspension according to claim 9, characterized in that, The mass ratio of sitagliptin phosphate resin sustained-release microcapsules to suspending agent is 4-6:1, and the suspending agent is preferably xanthan gum.

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