阅读说明：本技术 坎地沙坦酯氢***共无定形物及其制备方法 (Candesartan cilexetil hydrochlorothiazide co-amorphous substance and preparation method thereof ) 是由 高缘 王维洁 刘蕾 于 2020-08-11 设计创作，主要内容包括：本发明公开了一种坎地沙坦酯氢氯噻嗪共无定形物,由坎地沙坦酯与氢氯噻嗪结合形成,根据粉末X射线衍射图谱、DSC谱图、红外光谱可知,该共无定形物是一种完全不同于各单体及其物理混合物的新的固体形态。本发明将坎地沙坦酯与氢氯噻嗪制备成共无定形物,能显著提高坎地沙坦酯的溶解度与溶出速率,有望成为坎地沙坦酯/氢氯噻嗪复方片剂新的原料药固体形式,具有良好的应用开发前景。(The invention discloses a candesartan cilexetil hydrochlorothiazide co-amorphous substance, which is formed by combining candesartan cilexetil and hydrochlorothiazide, and is a new solid form completely different from each monomer and a physical mixture thereof according to a powder X-ray diffraction pattern, a DSC spectrogram and an infrared spectrum. The candesartan cilexetil and hydrochlorothiazide are prepared into the co-amorphous substance, so that the solubility and the dissolution rate of the candesartan cilexetil can be remarkably improved, the co-amorphous substance is expected to become a new raw material solid form of a candesartan cilexetil/hydrochlorothiazide compound tablet, and the co-amorphous substance has good application and development prospects.)

1. A candesartan cilexetil hydrochlorothiazide co-amorphous substance is characterized in that: formed by combining candesartan cilexetil with hydrochlorothiazide; the co-amorphous substance uses Cu-Kalpha radiation, has no sharp crystal diffraction peak in powder X-ray diffraction pattern, and has infrared absorption spectrum of 3373.5cm measured by potassium bromide tablet^-1、3261.6cm^-1、3063.0cm^-1、3030.2cm^-1、2985.8cm^-1、2939.5cm^-1、2860.4cm^-1、2351.2cm^-1、1747.5cm^-1、1600.9cm^-1、1552.7cm^-1、1516.0cm^-1、1471.7cm^-1、1454.3cm^-1、1431.2cm^-1、1336.7cm^-1、1280.7cm^-1、1244.1cm^-1、1215.2cm^-1、1172.7cm^-1、1159.2cm^-1、1122.6cm^-1、1112.9cm^-1、1074.4cm^-1、1035.8cm^-1、991.4cm^-1、908.5cm^-1、871.8 cm^-1、806.2 cm^-1、777.3 cm^-1、752.2 cm^-1、677.0 cm^-1、669.3cm^-1、644.2 cm^-1、603.7 cm^-1、540.1 cm^-1、520.8 cm^-1、482.2 cm^-1、457.1 cm^-1、418.6cm^-1Has an absorption peak.

2. The method for preparing the candesartan cilexetil hydrochlorothiazide co-amorphous substance as claimed in claim 1, wherein: the method comprises the following steps:

step 1, dissolving candesartan cilexetil and hydrochlorothiazide in an organic solvent to obtain a clear and transparent solution;

step 2, removing the solvent from the solution obtained in the step 1 through rotary evaporation to obtain a solid product;

and 3, drying the solid product obtained in the step 2 in vacuum to remove residual solvent, thus obtaining the candesartan cilexetil hydrochlorothiazide co-amorphous substance.

3. The method of claim 2, wherein: in the step 1, the molar ratio of candesartan cilexetil to hydrochlorothiazide is 1: 4-4: 1.

4. The method of claim 2, wherein: the organic solvent is one or a mixture of ethanol, methanol or acetonitrile.

5. The method of claim 4, wherein: the organic solvent is one or a mixed solvent of ethanol and methanol.

6. The method of claim 2, wherein: the temperature of rotary evaporation in the step 2 is 35-65 ℃.

7. A pharmaceutical composition characterized by: the candesartan cilexetil hydrochlorothiazide co-amorphous substance is included.

8. The pharmaceutical composition of claim 7, wherein: the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a candesartan cilexetil and hydrochlorothiazide co-amorphous substance formed by combining candesartan cilexetil and hydrochlorothiazide and a preparation method thereof.

Background

Candesartan cilexetil (Candesartan cilexetil) with the chemical name 2-ethoxy-1- [ [2'- (1H-tetrazol-5-yl) [1,1' -biphenyl]-4-yl]Methyl radical]-1H-benzimidazole-7-carboxylic acid-1- [ [ (cyclohexyloxy) carbonyl]Oxy radical]Ethyl ester of formula C₃₃H₃₄N₆O₆The chemical structure is shown as formula I. The candesartan cilexetil is one of main products of selective angiotensin II receptor Antagonists (ARBs), and plays roles of reducing blood pressure and promoting diuresis and natriuresis by specifically blocking angiotensin II-mediated vasoconstriction and aldosterone secretion. The candesartan cilexetil belongs to BCS II medicines, is insoluble in water, has low oral bioavailability, and is easy to cause angioedema, hyperkalemia and other adverse reactions.

Hydrochlorothiazide (Hydrochlorothiazide), chemical name is 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfamide-1, 1-dioxide, molecular formula is C₇H₈ClN₃O₄S₂The chemical structure is shown as formula II. Hydrochlorothiazide is a thiazide intermediate-effect diuretic, and through inhibiting the reabsorption of sodium chloride by the distal tubule, the sodium ion output is increased, so that the urine output is increased, and the blood volume load is reduced, thereby achieving the effect of lowering blood pressure. Hydrochlorothiazide belongs to BCS IV drugs, is slightly soluble in water, and a single preparation is easy to generate adverse reactions such as hypokalemia, hyperuricemia and the like after long-term administration.

Because the treatment of hypertension is long-term, single antihypertensive drugs cannot meet the clinical treatment requirements at present, and combined medication becomes a generally applicable initial treatment strategy. According to the guidelines of the institute of heart disease/hypertension (ESH/ESC) hypertension, the recommended combination of drugs for treating hypertension includes "thiazide diuretic in combination with angiotensin receptor blocker", "thiazide diuretic in combination with calcium channel blocker", etc. The Candesartan cilexetil/hydrochlorothiazide compound tablet jointly developed and developed by Wutian and Asrikang companies in Japan, the trade name is Atacand HCT, and belongs to a combined scheme of combining thiazide diuretic with angiotensin receptor blocker. The candesartan cilexetil is combined with hydrochlorothiazide, so that the drug effect can be enhanced, and the potassium loss effect caused by the hydrochlorothiazide can be effectively reversed, and the product is approved to be marketed by the United states Food and Drug Administration (FDA) in 2000.

The dissolution problem of insoluble drugs can be improved by applying crystal engineering technologies (such as eutectic, co-amorphous and the like), for example, the two BCS II drugs of valsartan and sabotaltra are prepared into the eutectic by Nowa company, so that the dissolution rate of the two drugs is remarkably improved, and simultaneously, a good synergistic pharmacological effect is generated, and the product of the sabotaltra valsartan sodium tablet (trade name Entresto) is approved by FDA to be on the market in 2015. The research of the invention finds that after the candesartan cilexetil and the hydrochlorothiazide are prepared into the co-amorphous substance, compared with the candesartan cilexetil, the solubility and the dissolution rate of the candesartan cilexetil can be obviously improved, the problem of low bioavailability caused by poor dissolution of the candesartan cilexetil is expected to be solved, and the co-amorphous substance becomes a new bulk drug solid form of the compound preparation.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a candesartan cilexetil hydrochlorothiazide co-amorphous substance and a preparation method thereof, the co-amorphous substance can obviously improve the solubility and dissolution rate of the candesartan cilexetil, is expected to become a new bulk drug solid form of a candesartan cilexetil/hydrochlorothiazide compound tablet, and has good application and development prospects.

In order to achieve the purpose, the invention adopts the following technical scheme:

a candesartan cilexetil hydrochlorothiazide co-amorphous substance is formed by combining candesartan cilexetil and hydrochlorothiazide; the co-amorphous substance uses Cu-Kalpha radiation, has no sharp crystal diffraction peak in powder X-ray diffraction pattern, and has infrared absorption spectrum of 3373.5cm measured by potassium bromide tablet^-1、3261.6cm^-1、3063.0cm^-1、3030.2cm^-1、2985.8cm^-1、2939.5cm^-1、2860.4cm^-1、2351.2cm^-1、1747.5cm^-1、1600.9cm^-1、1552.7cm^-1、1516.0cm^-1、1471.7cm^-1、1454.3cm^-1、1431.2cm^-1、1336.7cm^-1、1280.7cm^-1、1244.1cm^-1、1215.2cm^-1、1172.7cm^-1、1159.2cm^-1、1122.6cm^-1、1112.9cm^-1、1074.4cm^-1、1035.8cm^-1、991.4cm^-1、908.5cm^-1、871.8cm^-1、806.2cm^-1、777.3cm^-1、752.2cm^-1、677.0cm^-1、669.3cm^-1、644.2cm^-1、603.7cm^-1、540.1cm^-1、520.8cm^-1、482.2cm^-1、457.1cm^-1、418.6cm^-1Has an absorption peak.

The preparation method of the candesartan cilexetil hydrochlorothiazide co-amorphous substance comprises the following steps:

step 1, dissolving candesartan cilexetil and hydrochlorothiazide in an organic solvent to obtain a clear and transparent solution;

step 2, removing the solvent from the solution obtained in the step 1 through rotary evaporation to obtain a solid product;

and 3, drying the solid product obtained in the step 2 in vacuum to remove residual solvent, thus obtaining the candesartan cilexetil hydrochlorothiazide co-amorphous substance.

Further, the molar ratio of the candesartan cilexetil to the hydrochlorothiazide in the step 1 is 1: 4-4: 1.

Further, the organic solvent is one or a mixture of ethanol, methanol and acetonitrile.

Further, the organic solvent is one or a mixed solvent of ethanol and methanol.

Further, the temperature of rotary evaporation in the step 2 is 35-65 ℃. Preferably 45 to 55 ℃.

A pharmaceutical composition comprises the candesartan cilexetil hydrochlorothiazide co-amorphous form.

Further, the pharmaceutical composition also comprises a pharmaceutically acceptable carrier.

The pharmaceutical composition provided by the invention is prepared by taking the candesartan cilexetil hydrochlorothiazide amorphous substance as an active ingredient and a pharmaceutically acceptable carrier.

The pharmaceutical composition may be in any form suitable for administration: such as: tablets (including sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets), capsules (including hard capsules, soft capsules and sustained-release capsules), oral liquids, buccal agents, granules, dissolved medicines, pills, dropping pills, powders, ointments (including ointments and plasters), pellets, suspensions, powders, solutions, injections, suppositories, creams, sprays, drops, patches or troches.

For the pharmaceutical composition of the present invention, the preparation for oral administration may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary.

Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives (e.g. sodium starch glycolate). Suitable lubricants are, for example, magnesium stearate and the like. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate and the like.

The pharmaceutical composition of the present invention can be prepared into solid oral compositions by mixing, filling, tabletting and the like, which are methods commonly used in the art. Repeated mixing can result in a uniform distribution of the active in compositions that use large amounts of filler throughout.

Has the advantages that:

1. the candesartan cilexetil and hydrochlorothiazide co-amorphous substance is different from powder X-ray diffraction patterns, DSC (differential scanning calorimetry) spectra and infrared spectra of candesartan cilexetil, hydrochlorothiazide and physical mixtures thereof, so that the co-amorphous substance is a new solid form completely different from each monomer and the physical mixtures thereof.

2. The candesartan cilexetil and hydrochlorothiazide are prepared into the co-amorphous substance, so that the solubility and the dissolution rate of the candesartan cilexetil can be remarkably improved, the co-amorphous substance is expected to become a new raw material solid form of a candesartan cilexetil/hydrochlorothiazide compound tablet, and the co-amorphous substance has good application and development prospects.

Drawings

FIG. 1 is the results of the powder X-ray diffraction test in test example 1, in which: a is candesartan cilexetil crystal, b is hydrochlorothiazide crystal, c is a physical mixture of the candesartan cilexetil crystal and the hydrochlorothiazide crystal, and d is the candesartan cilexetil hydrochlorothiazide co-amorphous substance prepared in example 1.

FIG. 2 is the results of the differential scanning calorimetry test in test example 1, in which: a is candesartan cilexetil crystal, b is hydrochlorothiazide crystal, c is a physical mixture of the candesartan cilexetil crystal and the hydrochlorothiazide crystal, and d is the candesartan cilexetil hydrochlorothiazide co-amorphous substance prepared in example 1.

FIG. 3 shows the results of the IR test in test example 1, wherein: a is candesartan cilexetil crystal, b is hydrochlorothiazide crystal, c is a physical mixture of the candesartan cilexetil crystal and the hydrochlorothiazide crystal, and d is the candesartan cilexetil hydrochlorothiazide co-amorphous substance prepared in example 1.

Fig. 4 is a comparison of the dissolution curves of the supersaturated powders of the crystalline candesartan cilexetil and the amorphous candesartan cilexetil hydrochlorothiazide in the phosphate buffer solution (containing 0.35% Tween20) at pH6.5 in test example 2.

Fig. 5 is a comparison of characteristic dissolution rate curves of the candesartan cilexetil crystal and the candesartan cilexetil hydrochlorothiazide co-amorphous form in pH6.5 phosphate buffer (containing 0.35% Tween20) in test example 2.

Detailed Description

The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.