Complex disintegrant system for oral solid preparation and oral solid preparation comprising said complex disintegrant system

Abstract

A complex disintegrant composition for oral solid preparation, comprising a disintegrant and a disintegrating aid, the disintegrant being a hygroscopic expansion type disintegrant, the disintegrating aid being a soluble small molecule substance or a gas-producing type salt. An oral solid preparation, comprising an active ingredient, said complex disintegrant composition, an excipient and a lubricant.

Claims

1. An oral solid preparation comprising an active ingredient, a complex disintegrant system, an excipient and a lubricant; wherein the active ingredient is selected from the group consisting of compounds of following formula (I) and formula (II): ##STR00022## wherein in formula (I) and formula (II), R represents ##STR00023## wherein, a=0, 1, 2, 3, 4, 5 or 6; wherein, R.sub.1 represents C.sub.2-C.sub.8 alkyl, C.sub.2-C.sub.8 alkene, C.sub.2-C.sub.8 alkyne, ##STR00024## (CH.sub.2).sub.nO(CH.sub.2).sub.m, ##STR00025## phenyl, substituted phenyl, heteroaryl group or substituted heteroaryl group, wherein, C.sub.b, C.sub.c in ##STR00026## independently represent H or alkyl, wherein, b, c represent a number of carbon atoms, and are each independently selected from 0, 1, 2, 3, 4, 5 or 6; wherein n, m in (CH.sub.2).sub.nO(CH.sub.2).sub.m are each independently selected from 1, 2, 3, 4, 5 or 6; wherein R.sub.2 represents hydrogen, halogen, trifluoromethyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 alkyl, nitro, sulfonamide, amino or nitrile; wherein R.sub.3 represents C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, C.sub.2-C.sub.8 alkeneoxy, C.sub.2-C.sub.8 alkyneoxy, (C.sub.1-C.sub.6)O(C.sub.1-C.sub.6), ##STR00027## phenyl, substituted phenyl, heteroaryl group or substituted heteroaryl group, wherein, C.sub.b, C.sub.c in ##STR00028## independently represent H or alkyl, wherein, b, c represent a number of carbon atoms, and are each independently selected from 0, 1, 2, 3, 4, 5 or 6; wherein R.sub.4 represents phenyl, substituted phenyl, benzenesulfonyl, 5-6 membered heteroaryl group, 5-6 membered substituted heteroaryl group, nitrile, trifluoromethyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 nitrate, C.sub.1-C.sub.8 alkyl; wherein R.sub.5 represents phenyl, substituted phenyl, 5-6 membered heteroaryl group, 5-6 membered substituted heteroaryl group, nitrile, trifluoromethyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 nitrate, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkene, C.sub.1-C.sub.8 alkyne, ##STR00029## or (CH.sub.2).sub.nO(CH.sub.2).sub.m, wherein R.sub.3, R.sub.4, a, m, n are as defined above; wherein R.sub.6 and R.sub.7 represent hydrogen, C.sub.1-C.sub.8 alkoxy or C.sub.1-C.sub.8 alkyl; wherein R.sub.8 and R.sub.9 represent hydrogen, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 nitrate or C.sub.1-C.sub.8 alkyl; wherein the substituted phenyl refers to phenyl substituted by one or more selected from the group consisting of hydroxyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, nitro, amino, nitrile, trifluoromethyl and —CH═CHCO.sub.2R.sub.11, wherein each substituent may be same or different, wherein R.sub.11 represents hydrogen or C.sub.1-C.sub.6 alkyl; wherein the heteroaryl group refers to a -5-7 membered aryl group having 1 to 4 hetero atoms, each of which is independently selected from O, S or N; wherein the substituted heteroaryl group is a heteroaryl group substituted by at least one selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy and halogen, wherein each substituent may be same or different; wherein the complex disintegrant system consists of a disintegrant and a disintegrant assistant, the disintegrant being a hygroscopic swelling type disintegrant and the disintegrant assistant being a soluble small molecule or a gas generating type salt; wherein the hygroscopic swelling type disintegrant is selected from at least one of the group consisting of dry starch, croscarmellose sodium, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, methylcellulose, low substituted hydroxylpropyl cellulose, crospovidone, chitosan, and microcrystalline cellulose; wherein the gas generating salt is selected from at least one of the group consisting of sodium carbonate, potassium carbonate, zinc carbonate, magnesium carbonate, ammonium carbonate, sodium glycine carbonate, sodium sesquicarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and ammonium hydrogencarbonate; wherein the soluble small molecule is selected from at least one of the group consisting of sodium chloride, glucose, fructose, and xylitol; wherein the content of the active ingredient is about 10-20% by weight, the content of the disintegrant is about 4-15% by weight, the content of the disintegrant assistant is about 1-25% by weight, the content of the excipient is about 50-80% by weight, the content of the lubricant is about 1-5% by weight, and the weight ratio of the disintegrant to the disintegrant assistant is from 5:1 to 1:5.

2. The oral solid preparation according to claim 1, wherein the compound of formula (I) has one of structures shown below: ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## and the compound of formula (II) has one of structures shown below: ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040##

3. The oral solid preparation according to claim 1, wherein the excipient is selected from at least one of the group consisting of starch, lactose, mannitol, cellulose lactose, microcrystalline cellulose, calcium hydrogen phosphate and mannitol-starch complex; the lubricant is selected from at least one of the group consisting of talcum powder, magnesium stearate, calcium stearate, colloidal silica, hydrated silica, sodium octadecyl fumarate, polyethylene glycol, sodium stearyl fumarate, glyceryl monostearate and hydrogenated vegetable oil.

4. The oral solid preparation according to claim 1, further comprising a binder, wherein the binder is selected from at least one of the group consisting of starch and derivatives thereof (including but not limited to starch, pregelatinized starch, dextrin and maltodextrin), cellulose derivatives (including but not limited to methylcellulose, carboxy methylcellulose sodium, hydroxypropylcellulose, hypromellose, ethylcellulose and microcrystalline cellulose), natural and synthetic rubbers (including but not limited to gelatin, gum arabic, locust gum, peach glue), polyethylene glycol, povidone, glycerol dibehenate, carbomer, polyvinyl alcohol, poly(meth)acrylic resin, sugar alcohols (including but not limited to sucrose, liquid glucose, maltose alcohol), corn gluten, sodium alginate, and monolaurate and a content of the binder is about 0-15% by weight.

5. An oral solid preparation according to claim 1, wherein, the active ingredient is QR01019 or QR01019K as shown below: ##STR00041## and the oral solid preparation is a tablet.

6. The oral solid preparation according to claim 5, wherein the excipient is selected from at least one of the group consisting of starch, lactose, mannitol, cellulose lactose, microcrystalline cellulose, calcium hydrogen phosphate and mannitol-starch complex; the lubricant is selected from at least one of the group consisting of talcum powder, magnesium stearate, calcium stearate, colloidal silica, hydrated silica, sodium octadecyl fumarate, polyethylene glycol, sodium stearyl fumarate, glyceryl monostearate and hydrogenated vegetable oil.

7. The oral solid preparation according to claim 5, further comprising a binder, wherein the binder is selected from at least one of the group consisting of starch and derivatives thereof (including but not limited to starch, pregelatinized starch, dextrin and maltodextrin), cellulose derivatives (including but not limited to methylcellulose, carboxy methylcellulose sodium, hydroxypropylcellulose, hypromellose, ethylcellulose and microcrystalline cellulose), natural and synthetic rubbers (including but not limited to gelatin, gum arabic, locust gum and peach glue), polyethylene glycol, povidone, glycerol dibehenate, carbomer, polyvinyl alcohol, poly(meth)acrylic resin, sugar alcohols (including but not limited to sucrose, liquid glucose and maltose alcohol), corn gluten, sodium alginate, and monolaurate; and a content of the binder is about 0-15% by weight.

8. A method of antagonizing an angiotensin II receptor or treating hypertension, chronic heart failure, or diabetic nephropathy, comprising administering an effective amount of the oral solid preparation according to claim 1 to a subject in need thereof.

9. The oral solid preparation according to claim 2, wherein the excipient is selected from at least one of the group consisting of starch, lactose, mannitol, cellulose lactose, microcrystalline cellulose, calcium hydrogen phosphate and mannitol-starch complex; the lubricant is selected from at least one of the group consisting of talcum powder, magnesium stearate, calcium stearate, colloidal silica, hydrated silica, sodium octadecyl fumarate, polyethylene glycol, sodium stearyl fumarate, glyceryl monostearate and hydrogenated vegetable oil.

10. The oral solid preparation according to claim 2, further comprising a binder, wherein, the binder is selected from at least one of the group consisting of starch and derivatives thereof (including but not limited to starch, pregelatinized starch, dextrin and maltodextrin), cellulose derivatives (including but not limited to methylcellulose, carboxy methylcellulose sodium, hydroxypropylcellulose, hypromellose, ethylcellulose and microcrystalline cellulose), natural and synthetic rubbers (including but not limited to gelatin, gum arabic, locust gum, peach glue), polyethylene glycol, povidone, glycerol dibehenate, carbomer, polyvinyl alcohol, poly(meth)acrylic resin, sugar alcohols (including but not limited to sucrose, liquid glucose, maltose alcohol), corn gluten, sodium alginate, and monolaurate; and a content of the binder is about 0-15% by weight.

11. The oral solid preparation according to claim 3, further comprising a binder, wherein, the binder is selected from at least one of the group consisting of starch and derivatives thereof (including but not limited to starch, pregelatinized starch, dextrin and maltodextrin), cellulose derivatives (including but not limited to methylcellulose, carboxy methylcellulose sodium, hydroxypropylcellulose, hypromellose, ethylcellulose and microcrystalline cellulose), natural and synthetic rubbers (including but not limited to gelatin, gum arabic, locust gum, peach glue), polyethylene glycol, povidone, glycerol dibehenate, carbomer, polyvinyl alcohol, poly(meth)acrylic resin, sugar alcohols (including but not limited to sucrose, liquid glucose, maltose alcohol), corn gluten, sodium alginate, and monolaurate; and a content of the binder is about 0-15% by weight.

12. The oral solid preparation according to claim 6, further comprising a binder, wherein the binder is selected from at least one of the group consisting of starch and derivatives thereof (including but not limited to starch, pregelatinized starch, dextrin and maltodextrin), cellulose derivatives (including but not limited to methylcellulose, carboxy methylcellulose sodium, hydroxypropylcellulose, hypromellose, ethylcellulose and microcrystalline cellulose), natural and synthetic rubbers (including but not limited to gelatin, gum arabic, locust gum and peach glue), polyethylene glycol, povidone, glycerol dibehenate, carbomer, polyvinyl alcohol, poly(meth)acrylic resin, sugar alcohols (including but not limited to sucrose, liquid glucose and maltose alcohol), corn gluten, sodium alginate, and monolaurate; and a content of the binder is about 0-15% by weight.

13. A method of antagonizing an angiotensin II receptor or treating hypertension, chronic heart failure, or diabetic nephropathy, comprising administering an effective amount of the oral solid preparation according to claim 2 to a subject in need thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) In order to clearly illustrate the technical solution of the embodiments of the disclosure, the drawings of the embodiments will be briefly described in the following, it is obvious that the described drawings are only related to some embodiments of the disclosure and thus are not limitative of the disclosure.

(2) FIG. 1 is an H-NMR spectrum of QR01019K in example 1;

(3) FIG. 2 is an X-ray powder diffraction pattern of QR01019K in example 1.

DETAILED DESCRIPTION OF THE INVENTION

(4) In order to make objects, technical details and advantages of the embodiments of the disclosure apparent, the technical solutions of the embodiment will be described in a clearly and fully understandable way in connection with the drawings related to the embodiments of the disclosure. It is obvious that the described embodiments are just a part but not all of the embodiments of the disclosure. Based on the described embodiments herein, those skilled in the art can obtain other embodiment(s), without any inventive work, which should be within the scope of the disclosure.

Example 1: Preparation of QR01019K

(5) QR01019K (1.0 g) was dissolved in dichloromethane (5 ml), and the mixture was stirred at room temperature to form a solution, which was then added with potassium phthalimide (0.27 g), kept for 4 hours at room temperature, and cooled to −50° C., followed by filtration and solvent spin-drying to obtain an amorphous form of QR01019K.

(6) Melting point: 135-145° C.

(7) MS/HRMS m/z: 717 [M+H].sup.+; 677 [M−K].sup.−.

(8) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) δ: 1.44 (t, 3H), 1.46 (t, 3H), 2.38 (s, 3H), 2.41 (s, 3H), 2.44 (s, 3H), 4.64 (q, 2H), 5.29 (d, 1H), 5.32 (d, 1H), 5.52 (d, 1H), 5.56 (d, 1H), 6.86 (q, 1H), 6.90 (d, 2H), 7.18 (m, 2H), 7.22 (d, 2H), 7.33 (m, 1H), 7.36 (m, 1H), 7.46 (d, 1H), 7.52 (dd, 1H), 7.75 (d, 1H).

(9) The .sup.1H-NMR spectrum and the X-ray powder diffraction pattern are respectively shown in FIG. 1 and FIG. 2.

Example 2: Antihypertensive Efficacy Test of QR01019K in Spontaneously Hypertensive Rats

(10) 12-week-old spontaneously hypertensive rats (hereinafter referred to as SHR, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.) were anesthetized with 2.5% sodium pentobarbital for intraperitoneal injection. After that, the blood pressure sensing catheter of hypertension implant was inserted into their abdominal aorta, while the implant was fixed to the abdominal wall, and then postoperative daily care was performed after suturing. Rats with systolic blood pressure exceeding 160 mm Hg were divided into 3 groups (control group, QR01019 group and QR01019K group) wherein each group has 8 rats. The control group was administrated 0.5% sodium carboxymethylcellulose (hereinafter referred to as CMC-Na); QR01019 group and QR01019K group were respectively administered, both of which were dissolved by 0.5% CMC-Na, by intragastric administration, at a dose of 1 mg/kg (calculated by the effective dose of Azilsartan) and a volume calculated by 4 mL/kg. The systolic blood pressure and heart rate of SHR were compared before and after administration (the systolic blood pressure and heart rate of SHR before administration as reference value), which were detected three times at each time point with the average value recorded. The results are shown in Tables 1 and 2 below.

(11) TABLE-US-00001 TABLE 1 Systolic blood pressure change at each time point before and after oral administration of QR01019 and QR01019K (average (mmHg) ± standard error) 1 hour 3 hours 5 hours Before after after after adminis- adminis- adminis- adminis- Group tration tration tration tration Control group 0.0 ± 0.0  5.4 ± 7.1 −3.5 ± 4.6  4.5 ± 4.0 QR01019 group 0.0 ± 0.0 −4.9 ± 4.8 −22.0 ± 3.6* −30.5 ± 3.5* QR01019K group 0.0 ± 0.0 −7.0 ± 3.4 −34.3 ± 1.9* −46.5 ± 2.5* 7 hours 10 hours 24 hours after after after adminis- adminis- adminis- Group tration tration tration Control group  4.1 ± 3.2 −2.9 ± 2.3 −2.7 ± 6.4 QR01019 group −38.8 ± 2.3* −33.0 ± 1.7* −10.2 ± 2.1  QR01019K group −49.4 ± 4.1* −45.3 ± 3.3* −25.9 ± 3.4* *P < 0.01 (relative to the control group)

(12) It can be seen from the results in Table 1 that after 3 hours of administration, the systolic blood pressure of the QR01019 group or the QR01019K group groups is significantly decreased compared with the control group, and the drug efficacy peaks 5-7 hours after administration, and the QR01019K group is more potent with a longer-lasting antihypertensive effect than the QR01019 group.

(13) TABLE-US-00002 TABLE 2 Heart rates change before and after oral administration of QR01019 and QR01019K (average (times/minute) ± standard error) 1 hour 3 hours 5 hours Before after after after adminis- adminis- adminis- adminis- Group tration tration tration tration Control group 0.0 ± 0.0 0.14 ± 2.9 6.4 ± 2.8 −0.3 ± 2.7 QR01019 group 0.0 ± 0.0 −3.4 ± 2.6 −2.33 ± 2.6*   −6.5 ± 2.8* QR01019K group 0.0 ± 0.0 −3.6 ± 2.4 −5.0 ± 2.5* −10.1 ± 3.0* 7 hours 10 hours 24 hours after after after adminis- adminis- adminis- Group tration tration tration Control group −0.1 ± 2.9 −2.5 ± 2.5 4.3 ± 2.8 QR01019 group  −6.2 ± 3.0* −12.3 ± 2.8* −6.7 ± 2.6* QR01019K group −17.5 ± 3.0* −25.4 ± 2.4* −28.6 ± 8*   *P < 0.05 (relative to the one-way ANOVA of the control group).

(14) It can be seen from the results in Table 2 that after 3 hours of administration, the QR01019K group is more potent with a longer-lasting heart rate lowing effect, compared with the QR01019 group.

(15) The pharmacodynamic tests of QR01005K, QR01008K, QR01009K, QR01011K, QR01013K, QR01017K, QR01020K, QR01023K, QR01026K, QR01030K, QR01031K, QR01032K, QR01033K, QR01034K, QR01035K, QR01036K were also tested in the same manner as above, and these compounds were found to be similar to QR01019K, all of which have a more potent and longer-lasting antihypertensive and heart rate lowering effect than their corresponding unsalted compounds.

Example 3: Preparation and Disintegration Experiment of an Oral Solid Preparation

(16) The tablets of preparation examples 1-11 and comparative examples 1-11 were prepared according to the following three preparation methods. The formula composition and differences in tablet hardness and tablet weight of each preparation example and each comparative example were shown in Table 3 below.

(17) Preparation examples 1, 7, 8, 9 as well as comparative examples 1, 7, 8, 9 employed a powder tableting method: a 60-mesh sieve was selected according to the material properties, and the materials were sieved for use (in preparation example 7 and comparative example 7, the active ingredients were sifted together with the excipients, besides, the disintegrant and the disintegrant assistant were mixed together and sieved for use; while in the other preparation examples and comparative examples, above components were sieved separately); the active ingredient, the excipient, the disintegrant, and the disintegrant assistant (which was not added in comparative examples) were poured into a three-dimensional mixer for mixing, and then added with a lubricant for final mixing; the final mixed material was tableted in a rotary tabletting machine.

(18) A wet granulation method is employed in preparation examples 2, 4, 5, 10 as well as comparative examples 2, 4, 5, 10: a 60 mesh sieve was selected according to the material properties, and the materials were sieved for use; the active ingredient, the excipient, the disintegrant, and the disintegrant assistant (which was not added in comparative examples) were poured into a granulator, mixed together, added with an aqueous solution of the binder (5% aqueous solution of povidone was used in preparation example 2 and comparative example 2, 10% starch slurry was used in preparation example 4 and comparative example 4, and 8% starch slurry was used in preparation example 5 and comparative example 5), granulated and dried in fluidized bed; the dried granules were placed in a three-dimensional mixer, and then added with a lubricant for final mixing; the final mixed material was tableted in a rotary tablet press.

(19) A dry granulation method is employed in preparation examples 3, 6, 11 as well as comparative examples 3, 6, 11: a 60 mesh sieve was selected according to the material properties, and the materials were sieved for use; the active ingredient, the excipient, the disintegrant and the disintegrant assistant (which was not added in comparative examples) were poured into a three-dimensional mixer for mixing, and granulated in a dry granulator; the obtained granules were placed in a three-dimensional mixer, and then added with a lubricant for final mixing; the final mixed material was tableted in a rotary tablet press.

(20) The disintegration experiments were carried out according to the following experimental conditions, and the disintegration time of each preparation example and comparative example is shown in Table 3 below.

(21) Instrument: ZBS-6E intelligent disintegration tester (Tianjin Tianda Tianfa Technology Co., Ltd.)

(22) Method: hanging basket method

(23) Medium: 0.1 M HCl medium containing 0.5% Tween 80

(24) Round trip frequency: 30-32 times per minute

(25) Temperature: 37° C.

(26) TABLE-US-00003 TABLE 3 Tablet formula and disintegration time ingredient content/(mg/tablet) in comparative examples formula composition 1 2 3 4 5 6 7 8 9 10 11 active QR01019K 21 24 30 17 21 21 21 21 21 21 21 integrant excipient lactose 125 mannitol 50 110 156 108 117 137 137 cellulose lactose 120 60 20 microcrystalline 11 30 cellulose mannitol-starch 100 disintegrant cross-linked sodium 8 15 25 12 carboxymethyl cellulose cross-linked povidone 6 16 10 10 10 10 low substituted 15 hydroxypropyl cellulose binder povidone 15 starch 10 10 disintegrant sodium bicarbonate assitant sodium carbonate magnesium carbonate sodium glycine carbonate sodium sesquicarbonate sodium chloride glucose lubricant magnesium stearate 3 6 5 3 4.5 2 2 2 sodium stearyl fumarate 5 8 6 tablet hardness (kg/mm.sup.2) 3-10 3-10 4-6 4-6 4-6 4-6 3-10 4-6 4-6 4-6 4-6 tablet weight difference (within %) ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 disintegration time >15 min >15 min >15 min >15 min >15 min >15 min >15 min >15 min >15 min >15 min >15 min ingredient content/(mg/tablet) in preparation examples formula composition 1 2 3 4 5 6 7 8 9 10 11 active QR01019K 21 24 30 17 21 21 21 21 21 21 21 integrant excipient lactose 125 mannitol 50 110 156 108 117 137 137 cellulose lactose 120 60 20 microcrystalline 11 30 cellulose mannitol-starch 100 disintegrant cross-linked sodium 8 15 25 12 carboxymethyl cellulose cross-linked povidone 6 16 10 10 10 10 low substituted 15 hydroxypropyl cellulose l binder povidone 15 starch 10 10 disintegrant sodium bicarbonate 8 4.5 15 10 assitant sodium carbonate 15 15 magnesium carbonate 9 sodium glycine carbonate 20 sodium sesquicarbonate 4 sodium chloride 50 20 glucose 30 lubricant magnesium stearate 3 6 5 3 4.5 2 2 2 sodium stearyl fumarate 5 8 6 tablet hardness (kg/mm.sup.2) 3-10 3-10 4-6 4-6 4-6 4-6 3-10 4-6 4-6 4-6 4-6 tablet weight difference (within %) ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 ±5 disintegration time <60 s <60 s <60 s <60 s <60 s <60 s <60 s <60 s <120 s <120 s <120 s