CN1325054C - Cyclic dextrin inclusion compound of mintpress hydrochloride and its preparing method - Google Patents
Cyclic dextrin inclusion compound of mintpress hydrochloride and its preparing method Download PDFInfo
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- CN1325054C CN1325054C CNB2004100647982A CN200410064798A CN1325054C CN 1325054 C CN1325054 C CN 1325054C CN B2004100647982 A CNB2004100647982 A CN B2004100647982A CN 200410064798 A CN200410064798 A CN 200410064798A CN 1325054 C CN1325054 C CN 1325054C
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- minipress
- beta
- cyclodextrin
- clathrate
- schardinger dextrin
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Abstract
The present invention relates to a cyclodextrin inclusion compound of prazosin hydrochloride. The present invention comprises the following components: prazosin hydrochloride, and beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin is adopted, the mass ratio is 1: 20 to 1: 5, and the optimal ratio is 1: 10; auxiliary materials as the following can also be added: 400 0 to 10.0 of methyl cellulose, 400 0 to 50.0 of hydroxypropyl methyl cellulose, 0 to 15.0 of ethyl cellulose, 0 to 7.0 of lactose, 0 to 11.0 of microcrystalline cellulose, 0 to 18.0 of amylum pregelatinisatum, 0 to 1 of gum arabic and 0 to 0.5 of magnesium stearate. A preparation method of the cyclodextrin inclusion compound of prazosin hydrochloride comprises the following steps: the beta-cyclodextrin or the hydroxypropyl-beta-cyclodextrin is mixed with water into suspension or solution; 1/20 to 1/5 of the prazosin hydrochloride is added; the suspension or the solution and the prazosin hydrochloride are thoroughly mixed, filtered, pressed, washed, dried or directly dried and a solid compound is obtained. The present invention has the advantages that the drug release is stable, the function for lowering blood pressure is stable, and a person can conveniently take the drug.
Description
Technical field
The present invention relates to a kind of cyclodextrin clathrate of minipress, and the preparation method of this clathrate.
Background technology
Minipress is a selectivity postsynaptic a1 receptor blocking agent.This product vascular smooth muscle that can relax, the expansion peripheral vessels reduces peripheral vascular resistance, brings high blood pressure down.Expansion artery and vein reduce cardiac preload and afterload, make the left ventricular end diastolic drops, improve cardiac function.Can alleviate prostatic hyperplasia patient urinates difficulty by the a1 receptor of retardance neck of bladder, capsula prostatica and body of gland, urethra.
Symptoms such as this product is clinical to be used for that dysuria, nocturia that hyperplasia of prostate (prostate hyperplasia) causes increase, urgent micturition, weak stream of urine are weak; Sexual impotence and hyperpietic.This each edition of product state-promulgated pharmacopoeia is all recorded.
Minipress is white or off-white color crystalline powder, and is water insoluble.Use at present and be conventional tablet, specification: the 1mg/ sheet; The 2mg/ sheet; Dosage: 1. prostate hyperplasia: oral: initial dose 0.5mg, reactionless after, change the each 1mg of convention amount, every day 3-4 time.2. sexual impotence: 0.5mg first, as no significant discomfort reaction, dosage is increased to 1mg, every day 3 times.2 week backs as sexual function do not have and improve then that dosage is increased to 2mg, respectively 1 time sooner or later.Be February the course of treatment.3. hypertension: a 0.5-1mg, be adjusted into 6-15mg on the one by curative effect gradually every day 3 times, divide clothes 2-3 time.(first dose is 0.5mg, the preceding clothes of sleeping).Be adjusted into 6mg～15mg on the one by curative effect gradually, divide clothes 2～3 times, after every day, dosage surpassed 20mg, curative effect did not further increase.
The minipress half-life is shorter, T
1/2Be 2～3 hours, (Beagle dog: 3.79 hours; People: 3.0 hours), the medication of conventional tablet need every day is 3 times; " first dose of phenomenons " such as postural hypotensions may appear in medication first.Be steady blood pressure lowering, improve the compliance of patient's medication, Pfizer company has developed dispersion slow releasing tablet (2.5mg/ sheet, 5.0mg/ sheet), trade name Minipress
*(prescription constitutes XL: minipress, sheet (2.5mg/ sheet, 5.0mg/ sheet), trade name Minipress
*XL (prescription constitutes: minipress, polyethylene oxide, sodium chloride, hydroxy methocel, ferrum oxide, magnesium stearate, cellulose acetate, Polyethylene Glycol).Import China not as yet at present.Therefore, develop the minipress slow releasing agent very high clinical value and market efficiency are arranged.
Summary of the invention
The present invention seeks to adopt novel molecular microencapsulated material beta-schardinger dextrin-(β-CD) or HP-(HP-β-CD) and minipress effect, generate the solid clathrates of supermolecular, make the novel form of slow release, to reduce medicine blood drug level peak value, prolong half-life, reach steady blood drug level, reduce the patient and take number of times, the purpose that is convenient for carrying, uses.
Technical scheme of the present invention is:
The cyclodextrin clathrate of minipress comprises in its component:
Minipress, beta-schardinger dextrin-or HP-,
Both mass ratioes are 1: 20～1: 5 (best than 1: 10).
The enclose principle: molecular microcapsule material beta-schardinger dextrin-or HP-and minipress form stable clathrate, as shown in Figure 3.
The adjuvant that can add in above component has: hydroxypropyl methylcellulose, ethyl cellulose, microcrystalline Cellulose, lactose, micropowder silica gel, magnesium stearate, sodium alginate, dextrin, Polyethylene Glycol, calcium sulfate, citric acid, Powderd cellulose, magnesium silicate, Pulvis Talci etc.Can adopt in described each component a kind of, two or more.
Accessory formula is seen attached list.
| Numbering | Material | ％ |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 18 19 | Minipress β-CD or HP-β-CD HPMC 400 HPMCs 4000 ethyl cellulose lactose microcrystal cellulose amylum pregelatinisatum superfine silica gel powder dolomol sodium alginate dextrin polyethylene glycol calcium sulfate citric acid powdery cellulose magnesium silicate talcum powder | 3.0 15.0～60.0 0～6.5 0～25.5 0～6.0 0～5.0 0～9.0 0～13.5 0～1.0 0～0.5 0～11.5 0～28.5 0～3.0 0～2.0 0～4.0 0～16.5 0～1.0 0～0.5 |
The clathrate that generates by
1HNMR, IR, UV, X-ray and DSC spectrum are verified; The energy advantage of clathrate is verified by computer MM+ calculation procedure; Electronic spectrum proves that the equilibrium constant of above-mentioned enclose process reaches 160-1500M
-1, prove that clathrate makes minipress obtain enough stablizing.After clathrate dissolves in vivo, the medicine that progressively dissociates out performance drug effect, thus slowly discharge medicine.
The Preparation methods of cyclodextrin inclusion complexes of minipress, step comprises:
Beta-schardinger dextrin-or HP-are mixed with water, or make into suspended substance;
Adding mass ratio is the minipress of 1/20-1/5 amount, fully mixes;
Filter pressing, washing, drying or convection drying promptly get solid clathrates.
The solid clathrates of gained promptly has medicinal commodity value, but the above production method also can increase following steps:
The solid clathrates of gained with can tabletting or fill capsule after other adjuvant fully mixes.
The application recommends following prioritization scheme:
The Preparation methods of cyclodextrin inclusion complexes of minipress, step is as follows:
Beta-schardinger dextrin-or HP-are mixed with 1～10 times of amount pure water, make into suspended substance or solution;
(quality with cyclodextrin is 1) adds the minipress that mass ratio is the 1/20-1/5 amount, fully mixes, stirs 0.5～15 hour;
Filter pressing, the washing solids,
Be drying to obtain solid clathrates;
Clathrate is crossed 60～120 mesh sieves, fully mix, adopt wet method or dry granulation under 15～30 ℃ of conditions with other adjuvant shown in the last table, 60 ℃ of dryings 1～20 hour, granulate tabletting or fill capsule promptly get product.
Advantage of the present invention: clathrate self impels minipress to discharge and slows down, add the adjuvant (as microcrystalline Cellulose etc.) of control solid disintegrate in addition thus reach the specification requirement of slow release minipress.Simultaneously, method of the present invention is to prepare clathrate under the pure water condition, can avoid organic solvent residue, guarantees drug safety.Its effect has:
Drug release is steady: the ability that enclose material beta-schardinger dextrin-or HP-and minipress form supermolecule is stronger, the about 160-1500M of enclose constant K
-1, after clathrate became product according to the pharmaceutical formulation of subordinate list, the blood drug level peak value was expected to overcome the incidence rate of ordinary preparation " first dose of phenomenon " less than commercially available conventional tablet at present;
Hypotensive effect is steady, and longer duration has the good slow release effect;
Conveniently take: minipress/cyclodextrin clathrate drug disposition is longer than former preparation release time, and t1/2 reaches 6.4 hours, and the medicining times of design prescription is 1 time/day, the purpose that can reduce patient's medicining times, make things convenient for the patient to take medicine.The determination of plasma concentration figure of the oral this product of animal sees description of drawings.
Description of drawings
Fig. 1 is a process chart of the present invention;
Fig. 2 is the determination of plasma concentration figure of the oral this product of animal;
Fig. 3 is reactional equation figure of the present invention.
The specific embodiment
Embodiment 1, with reference to Fig. 1:
100 ml pure waters are mixed with 30 gram beta-schardinger dextrin-s, and heating adds 3 and restrains minipresses under 50 ℃ of temperature, fully mix and stirred 5 hours, cools off 24 hours down in 5 ℃ then; Filter solids washing 2 times.In 80 ℃ of dryings 24 hours, promptly get white solid inclusion compound.The clathrate of above-mentioned preparation prepares solid preparation according to following prescription:
| Numbering | Material | ％ |
| 1 2 3 4 5 6 7 8 9 10 | Minipress β-CD or HP-β-CD HPMC 400 HPMCs 4000 ethyl cellulose lactose microcrystal cellulose amylum pregelatinisatum superfine silica gel powder dolomols | 3.0 30.0 6.5 25.5 6.0 5 9 13.5 1 0.5 |
Each raw material is crossed 100 mesh sieves respectively in the table, and is standby.
Calculate and take by weighing the weight of required enclose intermediate according to drug content in the clathrate (promptly 1,2), take by weighing other each raw material in the prescription ratio.
Material 1～7 uniform mixing is 5 minutes in will writing out a prescription.Adopt wet method or dry granulation, get the homogeneous granule.
In hybrid particles, add material 8,9, uniform mixing 5 minutes.
Tabletting.
Quality inspection.
Packing.
Embodiment 2, and is substantially the same manner as Example 1, but replaces beta-schardinger dextrin-with HP-; Be that 30 ml pure waters are mixed heating with 30 gram HP-.
Embodiment 3, and with first step of embodiment 1, the method that promptly prepares white solid inclusion compound is basic identical, but no longer adds other adjuvants, promptly with this white solid inclusion compound as product.
Embodiment 4, and is substantially the same manner as Example 1, but is that 300 ml pure waters are mixed with 30 gram beta-schardinger dextrin-s, and heating adds 6 gram minipresses, the preparation clathrate under 50 ℃ of temperature.
Embodiment 6, and is substantially the same manner as Example 4, but beta-schardinger dextrin-is changed into HP-.
Embodiment 7, and is substantially the same manner as Example 5, but beta-schardinger dextrin-is changed into HP-.
Embodiment 8, and is substantially the same manner as Example 1, but the addition of other adjuvants is:
Sodium alginate 11.5
Dextrin 28.5
Polyethylene Glycol 3.0
Calcium sulfate 2.0
Citric acid 4.0
Powderd cellulose 16.5
Magnesium silicate 1.0
Pulvis Talci 0.5
Embodiment 9, and is substantially the same manner as Example 2, but the addition of other adjuvants is:
Sodium alginate 11.5
Dextrin 28.5
Polyethylene Glycol 3.0
Calcium sulfate 2.0
Citric acid 4.0
Powderd cellulose 16.5
Magnesium silicate 1.0
Pulvis Talci 0.5
Sodium alginate 11.5
Dextrin 28.5
Polyethylene Glycol 3.0
Calcium sulfate 2.0
Citric acid 4.0
Powderd cellulose 16.5
Magnesium silicate 1.0
Pulvis Talci 0.5
Embodiment 11, and is substantially the same manner as Example 5, but the addition of other adjuvants is:
Sodium alginate 11.5
Dextrin 28.5
Polyethylene Glycol 3.0
Calcium sulfate 2.0
Citric acid 4.0
Powderd cellulose 16.5
Magnesium silicate 1.0
Pulvis Talci 0.5
Embodiment 12, and is substantially the same manner as Example 6, but the addition of other adjuvants is:
Sodium alginate 11.5
Dextrin 28.5
Polyethylene Glycol 3.0
Calcium sulfate 2.0
Citric acid 4.0
Powderd cellulose 16.5
Magnesium silicate 1.0
Pulvis Talci 0.5
Embodiment 13, and is substantially the same manner as Example 7, but the addition of other adjuvants is:
Sodium alginate 11.5
Dextrin 28.5
Polyethylene Glycol 3.0
Calcium sulfate 2.0
Citric acid 4.0
Powderd cellulose 16.5
Magnesium silicate 1.0
Pulvis Talci 0.5
The invention is not restricted to these disclosed embodiments, the present invention will cover the scope described in the patent claims, and the various distortion of claim scope and equivalence variation.
Claims (4)
1, the cyclodextrin clathrate of minipress, its composition is:
Minipress and beta-schardinger dextrin-or HP-,
The mass ratio of described minipress and beta-schardinger dextrin-or HP-is 1: 20～1: 5;
The cyclodextrin clathrate of described minipress is meant: in the water suspension of beta-schardinger dextrin-or HP-, adding mass ratio is the minipress of 1/20-1/5 amount, fully mixes; Filter pressing, washing, drying or convection drying and the solid clathrates that obtains;
The equilibrium constant of this clathrate enclose process is 160-1500M
-1
2, according to the cyclodextrin clathrate of the described minipress of claim 1, it is characterized in that: the mass ratio of described minipress and beta-schardinger dextrin-or HP-is 1: 10.
3, according to the cyclodextrin clathrate of claim 1 or 2 described minipresses, it is characterized in that: also contain the adjuvant component, the mass percent of each adjuvant is:
Hydroxypropyl methylcellulose 400 0～10.0;
Hydroxypropyl methylcellulose 4,000 0～50.0;
Ethyl cellulose 0～15.0;
Lactose 0～7.0;
Microcrystalline Cellulose 0～11.0;
Amylum pregelatinisatum 0～18.0;
Micropowder silica gel 0～1;
Magnesium stearate 0～0.5.
4, the Preparation methods of cyclodextrin inclusion complexes of the described minipress of a kind of claim 1, step is as follows:
Beta-schardinger dextrin-or HP-are mixed with 1～10 times of amount pure water, make into suspended substance or solution;
Quality with cyclodextrin is 1, and adding mass ratio is the minipress of 1/20～1/5 amount, fully mixes, stirs 0.5～15 hour;
Filter pressing, the washing solids;
Be drying to obtain solid clathrates;
Clathrate is crossed 60～120 mesh sieves, fully mix, adopt wet method or dry granulation under 15～30 ℃ of conditions with other adjuvant shown in the last table, 60 ℃ of dryings 1～20 hour, granulate tabletting or fill capsule promptly get product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100647982A CN1325054C (en) | 2004-09-29 | 2004-09-29 | Cyclic dextrin inclusion compound of mintpress hydrochloride and its preparing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100647982A CN1325054C (en) | 2004-09-29 | 2004-09-29 | Cyclic dextrin inclusion compound of mintpress hydrochloride and its preparing method |
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|---|---|
| CN1615868A CN1615868A (en) | 2005-05-18 |
| CN1325054C true CN1325054C (en) | 2007-07-11 |
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| CNB2004100647982A Expired - Fee Related CN1325054C (en) | 2004-09-29 | 2004-09-29 | Cyclic dextrin inclusion compound of mintpress hydrochloride and its preparing method |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008110035A1 (en) * | 2007-03-14 | 2008-09-18 | Nanjing Normal University | A pharmaceutical composition containing inclusion compound of cyclodextrin and adefovir dipivoxil and preparative method thereof |
| US20130261142A1 (en) * | 2010-12-15 | 2013-10-03 | Hung-Cheng Lai | Compounds used for treating cancer and the use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61221122A (en) * | 1985-03-28 | 1986-10-01 | Tooa Eiyoo Kk | Prazosin preparation |
| JPS62158217A (en) * | 1986-01-07 | 1987-07-14 | Tooa Eiyoo Kk | Production of sustained release granule of prazosin |
| CN1258220A (en) * | 1997-06-05 | 2000-06-28 | 詹森药业有限公司 | Pharmaceutical compositions comprising cyclodextrins |
-
2004
- 2004-09-29 CN CNB2004100647982A patent/CN1325054C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61221122A (en) * | 1985-03-28 | 1986-10-01 | Tooa Eiyoo Kk | Prazosin preparation |
| JPS62158217A (en) * | 1986-01-07 | 1987-07-14 | Tooa Eiyoo Kk | Production of sustained release granule of prazosin |
| CN1258220A (en) * | 1997-06-05 | 2000-06-28 | 詹森药业有限公司 | Pharmaceutical compositions comprising cyclodextrins |
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| CN1615868A (en) | 2005-05-18 |
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