Candesartan cilexetil and hydrochlorothiazide compound preparation and preparation method thereof

Abstract

The invention discloses a candesartan cilexetil and hydrochlorothiazide compound preparation and a preparation method thereof. The preparation method comprises the following steps: preparing a solid dispersion from candesartan cilexetil and a Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol grafted copolymer)-TPGS (vitamin E polyethylene glycol succinate) dual-carrier system by adopting a low-temperature hot-melt extrusion technology, mixing the solid dispersion with hydrochlorothiazide granulated by a fluidized bed, and tabletting. The dissolution speed and bioavailability of candesartan cilexetil are improved, and the stability of the product is ensured.

Description

Technical Field

[0001] This invention belongs to the field of antihypertensive compound preparation technology, specifically relating to a formulation based on Soluplus. ® -TPGS dual-carrier system candesartan medoxomil / hydrochlorothiazide compound tablets and their low-temperature preparation process. Background Technology

[0002] Atacand HCT, a combination tablet of candesartan medoxomil / hydrochlorothiazide (16mg / 12.5mg) jointly developed by Takeda and AstraZeneca, was approved by the U.S. Food and Drug Administration on September 5, 2000, as a second-line treatment for hypertension. Atacand HCT is marketed in two fixed-dose formulations: 32mg candesartan medoxomil and 25mg hydrochlorothiazide, 32mg candesartan medoxomil and 12.5mg hydrochlorothiazide, and 16mg candesartan medoxomil and 12.5mg hydrochlorothiazide. This combination tablet has also been approved in the European Union for the treatment of hypertension. Multiple clinical trials have demonstrated that the candesartan medoxomil-hydrochlorothiazide combination has few side effects, good safety and tolerability, making it an ideal first-line treatment for hypertension.

[0003] Patent application CN101612151A discloses a solid oral dosage form containing candesartan medoxomil or candesartan medoxomil / hydrochlorothiazide and its preparation method. This solid oral dosage form containing candesartan medoxomil or candesartan medoxomil / hydrochlorothiazide comprises the following components by weight percentage: candesartan medoxomil 1%–25%, hydrochlorothiazide 0%–20%, filler 3%–75%, binder 0.5%–30%, stabilizer 0%–20%, and disintegrant 0%–10%. Wet granulation is employed, and preferably, an alcohol-containing solution is used for granulation.

[0004] However, candesartan medoxomil belongs to BCS Class II drugs, which are almost insoluble in water and easily crystallize in the pH environment of the gastrointestinal tract, resulting in oral bioavailability of less than 15%. The traditional technology has the following defects: (1) Physical mixture: Candesartan medoxomil and hydrochlorothiazide are both poorly soluble in water, and hydrochlorothiazide also has a certain degree of hydrophobicity. When it is combined with candesartan medoxomil to form tablets, its hydrophobic effect will further slow down the dissolution of candesartan medoxomil. Moreover, most literature reports that candesartan medoxomil, hydrochlorothiazide and excipients are granulated together, which increases the contact area between hydrochlorothiazide and candesartan medoxomil, which to some extent reduces the dissolution rate and bioavailability of candesartan medoxomil. (2) In the existing hot melt extrusion technology, the solid dispersions prepared by using single carriers such as Soluplus® and polyethylene glycol or Soluplus®-Poloxamer188 composite carriers all need to have a hot melt extrusion temperature (melting section >160℃) higher than the degradation temperature of candesartan medoxomil, which poses a risk of drug degradation. Summary of the Invention

[0005] To overcome the shortcomings of existing technologies, this invention provides a candesartan cilexetil and hydrochlorothiazide combination formulation, its preparation method, and its application. Candesartan cilexetil is formed into a solid dispersion (melt temperature ≤135℃) by low-temperature hot-melt extrusion with a mixed carrier system. This dispersion is then mixed with hydrochlorothiazide granules obtained through fluidized bed granulation and compressed into tablets. This improves the dissolution and bioavailability of candesartan cilexetil and enhances the stability of the hot-melt extruded candesartan cilexetil solid dispersion during tableting.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for preparing a candesartan medoxomil / hydrochlorothiazide combination preparation, comprising the following steps:

[0008] (1) Candesartan cilexetil and a dual-carrier system are hot-melt extruded to form a solid dispersion;

[0009] The drug loading of candesartan cilexetil in the solid dispersion is 25%–35%, and the dual carrier system accounts for 65%–75% of the total weight of the solid dispersion; this is Soluplus. ® A mixture of (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) and TPGS (vitamin E polyethylene glycol succinate) in a weight ratio of 5:1 to 7:1;

[0010] The hot melt extrusion process parameters are: feed speed 20-50 rpm; screw speed 150-350 rpm; temperature: 80±5℃ in the feeding section, 130±5℃ in the melting section, and 115±5℃ in the die section.

[0011] (2) Hydrochlorothiazide granules were obtained by fluidized bed granulation;

[0012] The hydrochlorothiazide granules are prepared by fluidized bed granulation of hydrochlorothiazide, filler, stabilizer, disintegrant and binder solution containing 4% to 4.5% hydroxypropyl cellulose (based on solution weight), and the particle size D50 after granulation is 80 to 120 μm.

[0013] The stabilizer is polyethylene glycol, the binder is an aqueous solution of hydroxypropyl cellulose containing 0%–0.5% colorant and 4%–4.5% hydroxypropyl cellulose, and the filler is a mixture of lactose and corn starch.

[0014] (3) After mixing the solid dispersion obtained in step (1) with the hydrochlorothiazide particles in step (2), the mixture is compressed into tablets, and the disintegration time at a hardness of 75N is ≤5 minutes.

[0015] This invention unexpectedly discovered that constructing the Soluplus®-TPGS dual-carrier system can significantly reduce the hot-melt extrusion temperature to below 135°C (see Table 5, Example 2), thereby effectively preventing drug degradation and improving product stability while ensuring high dissolution. Furthermore, referring to… Figures 4 to 7 As shown, candesartan cilexetil exists in three crystalline forms: Form I, Form II, and amorphous. Hot melt extrusion technology was used to fuse candesartan cilexetil with Soluplus... ® In the solid dispersion product prepared by the TPGS dual-carrier system, the crystal form of candesartan cilexetil changes from Form I to amorphous, significantly improving the dissolution rate of candesartan cilexetil. Furthermore, the hot-melt extruded solid dispersion did not undergo phase change (recrystallization) or physical collapse under mechanical pressure during subsequent co-compression with hydrochlorothiazide granules, specifically reflected in the absence of any increase in related substances in the resulting tablets during storage.

[0016] In the Soluplus®-TPGS dual-carrier system, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) provides strong molecular-level dispersion capabilities and inhibits drug crystallization. TPGS (vitamin E polyethylene glycol succinate), formed by the esterification of vitamin E succinate monoester and polyethylene glycol, serves as a liquid carrier with high plasticizing efficiency. It significantly reduces the glass transition temperature (Tg) and melt viscosity of Soluplus®, allowing hot melt extrusion to proceed smoothly at temperatures well below the degradation threshold of candesartan cilexetil.

[0017] In addition, TPGS itself is also an effective crystallization inhibitor. Working synergistically with Soluplus®, it constructs a strong hydrogen-bonded network and steric hindrance in the solid dispersion, not only more effectively maintaining the amorphous form of candesartan cilexetil during storage, but also enhancing its resistance to mechanically induced crystal transformations during tableting, solving the problem of tableting decomposition and ensuring the storage stability of the resulting compound formulation. Fluidized bed preparation of hydrochlorothiazide particles, with suitable compressibility, can effectively disperse and absorb the localized pressure applied to the candesartan cilexetil solid dispersion particles during tableting, physically avoiding the risk of pressure-induced crystal changes. Figure 8 As shown.

[0018] A candesartan medoxomil / hydrochlorothiazide combination preparation, comprising, by weight percentage, 9%–15% candesartan medoxomil, 6%–12% hydrochlorothiazide, and Soluplus. ® The composite carrier contains 20%–40% TPGS, 1%–5% stabilizer, 0%–0.5% colorant, 1%–6% binder, 25%–50% filler, 3%–5% disintegrant, and 0.5%–1.2% lubricant; TPGS accounts for 12%–20% of the total weight of the composite carrier.

[0019] The filler is lactose and corn starch; the binder is an aqueous solution of hydroxypropyl cellulose; the stabilizer is polyethylene glycol; the disintegrant is calcium carboxymethyl cellulose; and the lubricant is magnesium stearate.

[0020] Beneficial effects

[0021] Compared with the prior art, this application has the following advantages:

[0022] 1. Improved dissolution performance: In the FDA-approved dissolution medium (pH 6.5 phosphate - 0.35% polysorbate 20), candesartan medoxomil showed a cumulative dissolution rate of ≥50% at 5 minutes, ≥80% at 10 minutes, and ≥90% at 15 minutes, significantly faster than traditional physical mixtures (see [link to product description]). Figure 1 ).

[0023] 2. Improved Product Stability: This application employs a hot-melt extrusion process with a melt temperature ≤135℃, which not only effectively avoids drug degradation caused by high temperatures (see Table 6), but also successfully transforms the crystal form of candesartan cilexetil from Form I of the raw material to an amorphous form (see Table 6). Figure 7 Amorphous drugs possess higher energy and solubility, thus significantly improving dissolution rate and bioavailability. More importantly, as shown in the appendix... Figure 8 As shown, under accelerated stability test conditions, the amorphous form can exist stably without crystallization, which indicates that the formulation product of the present invention has good long-term physical stability.

[0024] 3. Improved bioavailability: Compared to the commercially available reference formulation, the Cmax of this invention is increased by ≥50%, and the AUC is... 0-t Increased by ≥55%, significantly improved bioavailability (see in vivo test results in beagle dogs, see...) ). Attached Figure Description

[0025] Figure 1 The results compare the in vitro dissolution curves of the tablets obtained in Comparative Example 1 and Examples 1, 2, and 3. The results show that the in vitro dissolution rate of Examples 1, 2, and 3 is significantly faster than that of Comparative Example 1, even when using Soluplus. ® -TPGS combined carrier, using hot melt extrusion process, can significantly improve the dissolution rate of candesartan cilexetil under the condition of ensuring 25% to 35% drug loading.

[0026] Figure 2 The results compare the in vitro dissolution curves of the tablets obtained in Comparative Example 1 and Examples 4 and 5. The results show that the in vitro dissolution rate of Examples 4 and 5 is significantly faster than that of Comparative Example 1, even when using Soluplus at a ratio of 5:1 to 7:1. ®- The TPGS composite carrier uses a hot melt extrusion process, which can significantly improve the dissolution rate of candesartan cilexetil.

[0027] Figure 3 The results of in vivo studies in beagle dogs comparing the commercially available reference formulation and the tablets obtained in Example 2 showed that, compared to the commercially available reference formulation, the formulation of Example 2 had a Cmax increase of ≥50% and an AUC increase of ≥50%. 0-t Improvement ≥55%. Even with Soluplus ® -TPGS combined carriers are solid dispersions of candesartan cilexetil prepared by hot melt extrusion process, which can significantly improve the bioavailability of candesartan cilexetil.

[0028] Figure 4 This is an X-ray powder diffraction pattern of the raw material for candesartan cilexetil. As shown in the figure, candesartan cilexetil has three crystal forms: Form I, Form II, and amorphous.

[0029] Figure 5 This is the X-ray powder diffraction pattern of the candesartan cilexetil raw material used in Example 2, for comparison. Figure 4 It is known that the crystal form of the raw material selected in this invention is Form I.

[0030] Figure 6 This is the blank excipient X-ray powder diffraction pattern for Example 2 with candesartan cilexetil removed from the formulation. It is used to evaluate the change in crystal form of the raw material before and after hot melt extrusion.

[0031] Figure 7 This is the X-ray powder diffraction pattern of Example 2, for comparison. Figure 4 , Figure 5 , Figure 6 It is known that this invention uses hot melt extrusion technology to combine candesartan cilexetil with Soluplus. ® The finished product was prepared by a solid dispersion using a TPGS dual-carrier system, in which the crystal form of candesartan cilexetil changed from Form I to amorphous, thus significantly improving the dissolution rate and bioavailability of candesartan cilexetil.

[0032] Figure 8 This is the X-ray powder diffraction pattern of Example 2 under accelerated conditions (40℃±2℃, 75%±5%RH) for 6 months, compared with the comparative example. Figure 7 It can be seen that the crystal form of the finished product did not change during the stability test, indicating that the present invention can guarantee the stability of the crystal form of the formulation. Detailed Implementation

[0033] The technical solution of the present invention will be described below with reference to specific comparative example 1 and embodiments:

[0034] Comparative Example 1:

[0035] Candesartan medoxomil and hydrochlorothiazide were prepared using a conventional mixed granulation process, and the formulation is shown in Table 1.

[0036] Table 1

[0037]

[0038] Preparation process: (1) Dissolve polyethylene glycol in 835g of water until completely dissolved, add hydroxypropyl cellulose and dissolve until clear to obtain a binder solution with added stabilizer; (2) Disperse yellow iron oxide and red iron oxide into the aqueous solution of (1) under stirring; (3) Mix lactose, corn starch, candesartan ester and hydrochlorothiazide and pass through a 30-mesh sieve and add to a fluidized bed. Spray the binder solution of (2) into the fluidized bed at a material temperature of 25-40℃ for granulation; (4) After granulation, dry to a moisture content of about 1% and pass through a 30-mesh sieve for granulation; (5) Add calcium carboxymethyl cellulose and magnesium stearate according to the weight of the particles and mix evenly; (6) Press into sheets with 8.5×5mm to obtain the final product.

[0039] Comparative Examples 2-4:

[0040] use The prescription shown represents a study of existing solid dispersion technology carriers.

[0041] Table 2

[0042]

[0043] Preparation process: (1) Preparation of candesartan cilexetil solid dispersion: After mixing candesartan cilexetil and carrier material evenly, it is fed into a twin-screw extruder. The feed speed is set to 20-50 rpm, the screw speed is 150-350 rpm, the feed section temperature is 100-120℃, the melting section temperature is 160-180℃, and the die section temperature is 140-160℃ for hot melt extrusion. The hot melt extruded material is then crushed by cold roller. (2) Preparation of hydrochlorothiazide granules: dissolve polyethylene glycol in water, add hydroxypropyl cellulose after complete dissolution, and add yellow iron oxide and red iron oxide under stirring until evenly dispersed to obtain the adhesive solution; mix lactose, corn starch and hydrochlorothiazide and add to the fluidized bed after passing through a 30-mesh sieve, and spray the adhesive solution into the fluidized bed at a material temperature of 25-40℃ for granulation; after granulation, dry to a moisture content of about 1% and pass through a 30-mesh sieve for granulation; (3) mix candesartan ester solid dispersion with hydrochlorothiazide granules, add calcium carboxymethyl cellulose and magnesium stearate according to the granule weight and mix evenly; (4) press into sheets with 8.5×5mm to obtain the product.

[0044] Examples 1-3:

[0045] use The formulations shown in Examples 1-3 illustrate the effect of different drug loadings on in vitro dissolution of tablets.

[0046] Table 3

[0047]

[0048] Preparation process:

[0049] (1) Preparation of candesartan cilexetil solid dispersion: Candesartan cilexetil, Soluplus®, and TPGS were mixed evenly and then fed into a twin-screw extruder. The feed speed was set to 20-50 rpm, the screw speed to 150-350 rpm, the feed section temperature to 80±5℃, the melt section temperature to 130±5℃, and the die section temperature to 115±5℃ for hot melt extrusion. The hot melt extrudate was then subjected to cold roller crushing. After cold roller crushing, the material was pulverized through a 40-mesh sieve.

[0050] (2) Preparation of hydrochlorothiazide granules: Dissolve polyethylene glycol in water, add hydroxypropyl cellulose after complete dissolution, and add yellow iron oxide and red iron oxide under stirring until evenly dispersed to obtain the binder solution; mix lactose, corn starch and hydrochlorothiazide and add to the fluidized bed after passing through a 30-mesh sieve; spray the binder solution into the fluidized bed at a material temperature of 25-40℃ for granulation; after granulation, dry to a moisture content of about 1% and granulate through a 30-mesh sieve.

[0051] (3) Mix candesartan cilexetil solid dispersion with hydrochlorothiazide particles, and add calcium carboxymethyl cellulose and magnesium stearate according to the particle weight and mix evenly.

[0052] (4) Use an 8.5×5mm stamping sheet to obtain the desired result.

[0053] Candesartan medoxomil / hydrochlorothiazide tablets from Comparative Example 1 and Examples 1-3 were used respectively. Dissolution was measured using 900 ml of a pH 6.5 phosphate buffer solution containing 0.35% polysorbate 20 as the dissolution medium via a paddle method at 50 rpm. The results are shown in Table 4.

[0054] Table 4

[0055]

[0056] Comparing the dissolution data of Comparative Example 1 and Examples 1, 2, and 3 within 5–60 min revealed that the dissolution rate of candesartan cilexetil in Examples 1, 2, and 3 was significantly faster than that in Comparative Example 1, even when using Soluplus. ® -TPGS combined carrier, using hot melt extrusion process, can significantly improve the dissolution rate of candesartan cilexetil under the condition of ensuring 25% to 35% drug loading.

[0057] The preparation parameters of candesartan cilexetil solid dispersions of Comparative Examples 2, 3, 4 and Example 2 are shown in Table 5:

[0058] Table 5

[0059]

[0060] Comparing the preparation parameters of candesartan cilexetil solid dispersions in Comparative Examples 2, 3, and 4 with those in Example 2, it was found that the temperatures in each stage of Example 2 were significantly lower than those in Comparative Examples 2, 3, and 4, even when using Soluplus. ® -TPGS composite carrier can significantly reduce the temperature of the hot melt extrusion feeding section, melting section and die section, which is advantageous for ensuring product stability.

[0061] Take the candesartan medoxomil / hydrochlorothiazide tablets from Example 2 and place them under high temperature (60°C) for 30 days, high humidity (90%RH) for 30 days, and light exposure (4500±500 Lux, total illuminance not less than 1.2×10⁻⁶). 6 Lux·hr, near-ultraviolet energy not less than 200 W·hr / m 2 The results of the relevant substance tests after 10 days are shown in Table 6:

[0062] Table 6

[0063]

[0064] The results of the investigation of the influencing factors of the sample in Example 2 showed that under the conditions of each influencing factor, no significant changes were observed in each impurity compared with day 0. That is, the tablets made by combining the candesartan cilexetil solid dispersion prepared with Soluplus®-TPGS as carrier and melt temperature ≤135℃ with hydrochlorothiazide granules by fluidized bed granulation have good product stability.

[0065] Examples 4 and 5:

[0066] Using the formulations shown in Table 7, the effects of different carrier material ratios on in vitro dissolution in Examples 4 and 5 were compared.

[0067] Table 7

[0068]

[0069] Preparation process: Same as the preparation process in Examples 1-3.

[0070] Candesartan medoxomil / hydrochlorothiazide tablets from Comparative Example 1 and Examples 4-5 were used. Dissolution was measured using a paddle method at 50 rpm in 900 ml of a pH 6.5 phosphate buffer solution containing 0.35% polysorbate 20. The results are shown in Table 8.

[0071] Table 8

[0072]

[0073] Comparing the dissolution data of Comparative Example 1 and Examples 4-5, it was found that the dissolution rate of Examples 4-5 was significantly faster than that of Comparative Example 1, indicating that the hot melt extrusion process ensured the dissolution rate of Soluplus. ® When the TPGS ratio is 5:1 to 7:1, the dissolution rate of candesartan medoxomil can be significantly improved.

[0074] Take candesartan medoxomil / hydrochlorothiazide tablets from Example 2 and compare them with a commercially available reference formulation (trade name: Blopress). ® (Manufacturer: Takeda GmbH; Batch No.: 510313) Pharmacokinetic studies were conducted in beagle dogs, which were administered 16 mg candesartan cilexetil / 12.5 mg hydrochlorothiazide. Specific results for the candesartan cilexetil component are shown in Table 9.

[0075] Table 9

[0076]

[0077] The results showed that, compared with the commercially available reference formulation, the formulation in Example 2 had a Cmax increase of ≥50% and an AUC increase of ≥50%. 0-t Improvement ≥55%. Even with Soluplus ® -TPGS combined carriers are solid dispersions of candesartan cilexetil prepared by hot melt extrusion process, which can significantly improve the bioavailability of candesartan cilexetil.

Claims

1. A method for preparing a candesartan medoxomil / hydrochlorothiazide compound preparation, characterized in that: The steps are as follows: (1) Candesartan cilexetil and a dual-carrier system are hot-melt extruded to form a solid dispersion; The drug loading of candesartan cilexetil in the solid dispersion is 25%–35%, and the dual carrier system accounts for 65%–75% of the total weight of the solid dispersion; this is Soluplus. ® A mixture of (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) and TPGS (vitamin E polyethylene glycol succinate) in a weight ratio of 5:1 to 7:1; (2) Hydrochlorothiazide granules were obtained by fluidized bed granulation; (3) After mixing the solid dispersion obtained in step (1) with the hydrochlorothiazide particles in step (2), the mixture is compressed into tablets, and the disintegration time at a hardness of 75N is ≤5 minutes.

2. The preparation method of the candesartan medoxomil / hydrochlorothiazide compound preparation according to claim 1, characterized in that: In step 1, the hot melt extrusion process parameters are: feed speed 20-50 rpm; screw speed 150-350 rpm; temperature: 80±5℃ in the feeding section, 130±5℃ in the melting section, and 115±5℃ in the die section.

3. The preparation method of the candesartan medoxomil / hydrochlorothiazide compound preparation according to claim 1, characterized in that: In step 2, the hydrochlorothiazide particles are prepared by fluidized bed granulation of hydrochlorothiazide, filler, stabilizer, disintegrant and binder solution containing 4% to 4.5% hydroxypropyl cellulose (based on solution weight), and the particle size D50 after granulation is 80 to 120 μm.

4. The preparation method of the candesartan medoxomil / hydrochlorothiazide compound preparation according to claim 3, characterized in that: The stabilizer is polyethylene glycol, the binder is an aqueous solution of hydroxypropyl cellulose containing 0%–0.5% colorant and 4%–4.5% hydroxypropyl cellulose, and the filler is a mixture of lactose and corn starch.

5. A candesartan medoxomil / hydrochlorothiazide combination preparation, characterized in that: The raw materials, by weight percentage, include candesartan medoxomil 9%–15%, hydrochlorothiazide 6%–12%, and Soluplus. ® The composite carrier contains 20%–40% TPGS, 1%–5% stabilizer, 0%–0.5% colorant, 1%–6% binder, 25%–50% filler, 3%–5% disintegrant, and 0.5%–1.2% lubricant; TPGS accounts for 12%–20% of the total weight of the composite carrier.

6. The method for preparing a candesartan medoxomil / hydrochlorothiazide compound preparation according to claim 5, characterized in that: The filler is lactose and corn starch; the binder is an aqueous solution of hydroxypropyl cellulose; the stabilizer is polyethylene glycol; the disintegrant is calcium carboxymethyl cellulose; and the lubricant is magnesium stearate.

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