CN109010313A - A kind of preparation method of alfuzosin hydrochloride sustained release preparation - Google Patents

A kind of preparation method of alfuzosin hydrochloride sustained release preparation Download PDF

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Publication number
CN109010313A
CN109010313A CN201711109359.2A CN201711109359A CN109010313A CN 109010313 A CN109010313 A CN 109010313A CN 201711109359 A CN201711109359 A CN 201711109359A CN 109010313 A CN109010313 A CN 109010313A
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solution
alfuzosin hydrochloride
preparation
sustained release
temperature
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刘丽
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a kind of preparation method of alfuzosin hydrochloride sustained release preparation, and alfuzosin hydrochloride is dissolved in 95% ethyl alcohol, obtains solution A, hydroxypropylβ-cyclodextrin is added in solution A and mannitol obtains solution B；Polylactic acid and polyethylene glycol 200 are dissolved in acetone and obtain solution C, solution B and solution C are mixed into obtain solution D, solution D is transferred in magnetic stirring apparatus, continuous stirring solution D12 hours, solution D temperature is down to 0 DEG C~1 DEG C in 2 hours again and stands 12 hours, maintains solution D temperature at 0 DEG C~1 DEG C during standing.Solution D is heated after standing 12 hours, is continuously stirred when solution D temperature rises to 15 DEG C~18 DEG C, solution D temperature is controlled at 15 DEG C~18 DEG C when stirring, obtains alfuzosin hydrochloride sustained release preparation with low temperature spray drying legal system after continuously stirring 12 hours.Capsule material dosage of the present invention is moderate, and dry materials temperature is low, and obtained carrying medicine is uniform in size, and drug release is stablized, and has the characteristics that sustained release.

Description

A kind of preparation method of alfuzosin hydrochloride sustained release preparation
Technical field:
The present invention relates to a kind of pharmaceutical preparation of medicine-carrying polymer preparation more particularly to a kind of alfuzosin hydrochloride sustained release systems The preparation method of agent.
Background technique:
Hydroxypropylβ-cyclodextrin is a kind of ideal injection solubilizer and drug excipient in medical industry.It can be with The water solubility of insoluble drug is improved, increases medicine stability, improve drug bioavailability, the curative effect of medicament is made to increase or take Dosage is reduced, and adjustable or control drug rate of release reduces poisonous side effect of medicine.Can be used for oral drugs, injection, Mucoadhesive delivery system (including schneiderian membrane, rectum, cornea etc.), Transdermal absorption drug delivery system, lipophilicity targeted drug carrier.
Polylactic acid has tight security to human body, has good biocompatibility and biodegradability, is widely used In medicament slow release.Currently, the preparation method of polylactic acid drug bearing microsphere mainly has phase separation method, emulsion-solvent evaporation method, spray-on process Deng.
Alfuzosin hydrochloride is a kind of quinazoline derivative, optionally blocks and is distributed in bladder, urethra and forefront The postsynaptic alpha adrenergic receptor of gland trigonum, the lower urinary tract smooth muscle contraction that antagonism this receptor mediates, so as to improve benign The dysuric related symptoms of Patients with Prostatic Hyperplasia.For alleviating benign prostate hyperplasia shape.Alfuzosin hydrochloride is oral Constant slow release at a predetermined rate after sustained release preparation administration, can rapid delivery of pharmaceuticals rather than conventional formulation.With it is corresponding Ordinary preparation, such as fast-release tablet, capsule, oral solution are compared, and the compliance of patient can be improved and increase curative effect of medication.Sustained release preparation Major advantage be the blood concentration peak valley phenomenon that can be reduced dosage frequency and avoiding and take ordinary preparation appearance.Sustained release system Agent can keep blood concentration to stablize within the scope of effective blood drug concentration within the relatively long time, to improve the peace of drug Quan Xing.Alfuzosin hydrochloride sustained release preparation mainly uses skeleton agent technology to produce at present, commonly uses ethyl cellulose, acrylic acid tree Rouge, lactose, the auxiliary materials such as microcrystalline cellulose.But drug release changes during there is burst release and storage with the dosage form that such technology produces Risk, and supplementary product consumption is big, is unfavorable for taking orally.A kind of safe and effective, reliable in quality, production efficiency are provided to this for clinic Height, supplementary product consumption is moderate, and the stable alfuzosin hydrochloride sustained release preparation of drug release is necessary, in consideration of it, proposing the present invention.
Summary of the invention:
The technical problem to be solved by the present invention lies in overcoming the defects of the prior art, provides a kind of safe and effective, quality Reliably, high production efficiency, supplementary product consumption is moderate, the stable alfuzosin hydrochloride sustained release preparation and preparation method thereof of drug release.
The technical problems to be solved by the invention are realized using following technical scheme.
A kind of alfuzosin hydrochloride sustained release preparation, which is characterized in that the sustained release preparation is by alfuzosin hydrochloride, hydroxypropyl beta- Cyclodextrin, polylactic acid, mannitol, polyethylene glycol 200,95% ethyl alcohol and acetone composition.The alfuzosin hydrochloride is sustained system Agent each component contains 95% ethyl alcohol 110~130 by weight hydrochloric Alfuzosin 100, containing hydroxypropylβ-cyclodextrin 100~ 130, contain mannitol 20~30, contain acetone 120~150, contain polylactic acid 120~150, contains polyethylene glycol 200 20~40, it is described Polylactic acid relative molecular weight is 5000~20000.
It is a further object to provide a kind of method for being prepared into alfuzosin hydrochloride sustained release preparation, feature exists In the specific steps of this method are as follows:
1) alfuzosin hydrochloride is dissolved in 95% ethyl alcohol, obtains alfuzosin hydrochloride solution, is denoted as solution A；
2) hydroxypropylβ-cyclodextrin and mannitol are added in solution A, obtains solution B；
3) polylactic acid and polyethylene glycol are dissolved in acetone, obtain polylactic acid and polyethylene glycol 200 solution, is denoted as solution C；
4) solution B and solution C are mixed, obtains solution D；
5) solution D is transferred in magnetic stirring apparatus, controls the temperature of solution D at 15 DEG C~18 DEG C, continuous stirring solution D12 hours, then solution D temperature is down to 0 DEG C~1 DEG C in 2 hours and stands 12 hours, solution D temperature is maintained during standing At 0 DEG C~1 DEG C；
6) solution D for obtaining step 5 heats, and continuously stirs when solution D temperature rises to 15 DEG C~18 DEG C 12 hours, The control of solution D temperature is at 15 DEG C~18 DEG C when stirring；
7) solution D that step 6 obtains is obtained into alfuzosin hydrochloride sustained release preparation with low temperature spray drying legal system.
Alfuzosin hydrochloride sustained release preparation of the invention is through the body with commercially available same dosage form alfuzosin hydrochloride sustained release preparation Outer cumulative release amount comparative study, it was demonstrated that alfuzosin hydrochloride sustained release preparation drug release of the invention is more stable, slow-release function More preferably.And preparation method high production efficiency, capsule material dosage is moderate, and dry materials temperature is low, and obtained carrying medicine is uniform in size, Encapsulation rate is greater than 80%, and drugloading rate is greater than 50%.
Detailed description of the invention
Curve a is the extracorporeal accumulating released medicine curve of 1 gained preparation of the embodiment of the present invention in Fig. 1, and curve b is commercially available identical The extracorporeal accumulating released medicine curve of dosage form alfuzosin hydrochloride sustained release preparation.In Fig. 1, abscissa is time (hour), indulges and sits It is designated as cumulative release amount (%).
Curve a is the extracorporeal accumulating released medicine curve of 2 gained preparation of the embodiment of the present invention in Fig. 2, and curve b is commercially available identical The extracorporeal accumulating released medicine curve of dosage form alfuzosin hydrochloride sustained release preparation.In Fig. 2, abscissa is time (hour), indulges and sits It is designated as cumulative release amount (%).
Curve a is the extracorporeal accumulating released medicine curve of 3 gained preparation of the embodiment of the present invention in Fig. 3, and curve b is commercially available identical The extracorporeal accumulating released medicine curve of dosage form alfuzosin hydrochloride sustained release preparation.In Fig. 3, abscissa is time (hour), indulges and sits It is designated as cumulative release amount (%).
Specific embodiment:
In order to be easy to understand the technical means, the creative features, the aims and the efficiencies achieved by the present invention, tie below Specific embodiment is closed, the present invention is further explained.
For the consistency of guarantee test result, the embodiment of the present invention has used the raw material of same batch, auxiliary material, and uses Consistent production technology prepares alfuzosin hydrochloride sustained release preparation.
Embodiment one:
1) 100g alfuzosin hydrochloride is dissolved in 110g95% ethyl alcohol, obtains alfuzosin hydrochloride ethanol solution, be denoted as molten Liquid A；
2) 100g hydroxypropylβ-cyclodextrin and 20g mannitol are added in solution A, obtains solution B；
3) 120g polylactic acid and 20g polyethylene glycol 200 are dissolved in 120g acetone, obtain polylactic acid and polyethylene glycol 200 is molten Liquid is denoted as solution C；
4) solution B and solution C are mixed, obtains solution D；
5) solution D is transferred in magnetic stirring apparatus, controls the temperature of solution D at 15 DEG C~18 DEG C, continuous stirring solution D12 hours, then solution D temperature is down to 0 DEG C~1 DEG C in 2 hours and stands 12 hours, solution D temperature is maintained during standing At 0 DEG C~1 DEG C；
6) solution D for obtaining step 5 heats, and continuously stirs when solution D temperature rises to 15 DEG C~18 DEG C 12 hours, The control of solution D temperature is at 15 DEG C~18 DEG C when stirring；
7) solution D that step 6 obtains is obtained into alfuzosin hydrochloride sustained release preparation with low temperature spray drying legal system, be spray-dried Temperature control at 55 DEG C, nozzle diameter: 0.5mm, vacuum degree: 0.03MPA, flow: 500ml/ hours.
Sample obtained by low temperature spray drying is taken, it is 80.15% that gained sample, which measures encapsulation rate, carrying drug ratio 50.24%, body Outer release experiment proves this preparation energy slow release alfuzosin hydrochloride, alfuzosin hydrochloride finally discharge reachable 90% with On, see Fig. 1.
Embodiment two:
1) 100g alfuzosin hydrochloride is dissolved in 120g95% ethyl alcohol, obtains alfuzosin hydrochloride ethanol solution, be denoted as molten Liquid A；
2) 115g hydroxypropylβ-cyclodextrin and 25g mannitol are added in solution A, obtains solution B；
3) 135g polylactic acid and 30g polyethylene glycol 200 are dissolved in 135g acetone, obtain polylactic acid and polyethylene glycol 200 is molten Liquid is denoted as solution C；
4) solution B and solution C are mixed, obtains solution D；
5) solution D is transferred in magnetic stirring apparatus, controls the temperature of solution D at 15 DEG C~18 DEG C, continuous stirring solution D12 hours, then solution D temperature is down to 0 DEG C~1 DEG C in 2 hours and stands 12 hours, solution D temperature is maintained during standing At 0 DEG C~1 DEG C；
6) solution D for obtaining step 5 heats, and continuously stirs when solution D temperature rises to 15 DEG C~18 DEG C 12 hours, The control of solution D temperature is at 15 DEG C~18 DEG C when stirring；
7) solution D that step 6 obtains is obtained into alfuzosin hydrochloride sustained release preparation with low temperature spray drying legal system, be spray-dried Temperature control at 55 DEG C, nozzle diameter: 0.75mm, vacuum degree: 0.035MPA, flow: 700ml/ hours.
Sample obtained by low temperature spray drying is taken, it is 80.22% that gained sample, which measures encapsulation rate, carrying drug ratio 51.41%, body Outer release experiment proves this preparation energy slow release alfuzosin hydrochloride, alfuzosin hydrochloride finally discharge reachable 90% with On, see Fig. 2.
Embodiment three:
1) 100g alfuzosin hydrochloride is dissolved in 130g95% ethyl alcohol, obtains alfuzosin hydrochloride ethanol solution, be denoted as molten Liquid A；
2) 130g hydroxypropylβ-cyclodextrin and 30g mannitol are added in solution A, obtains solution B；
3) 150g polylactic acid and 40g polyethylene glycol 200 are dissolved in 150g acetone, obtain polylactic acid and polyethylene glycol 200 is molten Liquid is denoted as solution C；
4) solution B and solution C are mixed, obtains solution D；
5) solution D is transferred in magnetic stirring apparatus, controls the temperature of solution D at 15 DEG C~18 DEG C, continuous stirring solution D12 hours, then solution D temperature is down to 0 DEG C~1 DEG C in 2 hours and stands 12 hours, solution D temperature is maintained during standing At 0 DEG C~1 DEG C；
6) solution D for obtaining step 5 heats, and continuously stirs when solution D temperature rises to 15 DEG C~18 DEG C 12 hours, The control of solution D temperature is at 15 DEG C~18 DEG C when stirring；
7) solution D that step 6 obtains is obtained into alfuzosin hydrochloride sustained release preparation with low temperature spray drying legal system,
The temperature of spray drying is controlled at 60 DEG C, and nozzle diameter: 1mm, vacuum degree: 0.04MPA, flow: 1000ml/ is small When.
Sample obtained by low temperature spray drying is taken, it is 81.01% that gained sample, which measures encapsulation rate, carrying drug ratio 51.43%, body Outer release experiment proves this preparation energy slow release alfuzosin hydrochloride, alfuzosin hydrochloride finally discharge reachable 90% with On, see Fig. 3.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry For personnel it should be appreciated that the present invention is not limited to the above embodiments, described in the above embodiment and specification is only the present invention Preference, be not intended to limit the invention, without departing from the spirit and scope of the present invention, the present invention also has various Changes and improvements, these changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention is by institute Attached claims and its equivalent thereof.

Claims (5)

1. a kind of preparation method of alfuzosin hydrochloride sustained release preparation, it is characterised in that the alfuzosin hydrochloride sustained release preparation It is made of alfuzosin hydrochloride, hydroxypropylβ-cyclodextrin, polylactic acid, mannitol, polyethylene glycol 200,95% ethyl alcohol, acetone.
2. the preparation method of alfuzosin hydrochloride sustained release preparation as described in claim 1, it is characterised in that the steps include:
1) alfuzosin hydrochloride is dissolved in 95% ethyl alcohol, obtains alfuzosin hydrochloride solution, is denoted as solution A；
2) hydroxypropylβ-cyclodextrin and mannitol are added in solution A, obtains solution B；
3) polylactic acid and polyethylene glycol are dissolved in acetone, obtain polylactic acid and polyethylene glycol 200 solution, is denoted as solution C；
4) solution B and solution C are mixed, obtains solution D；
5) solution D is transferred in magnetic stirring apparatus, controls the temperature of solution D at 15 DEG C~18 DEG C, continuous stirring solution D12 is small When, then solution D temperature is down to 0 DEG C~1 DEG C in 2 hours and stands 12 hours, maintain solution D temperature at 0 DEG C during standing ~1 DEG C；
6) solution D for obtaining step 5 heats, and continuously stirs when solution D temperature rises to 15 DEG C~18 DEG C 12 hours, stirs When solution D temperature control at 15 DEG C~18 DEG C；
7) solution D that step 6 obtains is obtained into alfuzosin hydrochloride sustained release preparation with low temperature spray drying legal system.
3. alfuzosin hydrochloride sustained release preparation each component as claimed in claim 1 or 2 is by weight hydrochloric Alfuzosin 100, contain 95% ethyl alcohol 110~130, contain hydroxypropylβ-cyclodextrin 100~130, contains mannitol 20~30, containing acetone 120~ 150, contain polylactic acid 120~150, contains polyethylene glycol 200 20~40.
4. the preparation method of alfuzosin hydrochloride sustained release preparation as claimed in claim 1 or 2, it is characterised in that the phase of polylactic acid It is 5000~20000 to molecular weight.
5. the preparation method of alfuzosin hydrochloride sustained release preparation as claimed in claim 3, it is characterised in that low temperature spray drying Temperature be 55 DEG C~60 DEG C, nozzle diameter be 0.5mm~1mm, hothouse vacuum degree be 0.03MPA~0.04MPA, solution D Flow is 500ml/ hours~1000ml/ hours.
CN201711109359.2A 2017-11-11 2017-11-11 A kind of preparation method of alfuzosin hydrochloride sustained release preparation Withdrawn CN109010313A (en)

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Application publication date: 20181218