CN108992424A - A kind of preparation method of nevirapine sustained release preparation - Google Patents

A kind of preparation method of nevirapine sustained release preparation Download PDF

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Publication number
CN108992424A
CN108992424A CN201711109748.5A CN201711109748A CN108992424A CN 108992424 A CN108992424 A CN 108992424A CN 201711109748 A CN201711109748 A CN 201711109748A CN 108992424 A CN108992424 A CN 108992424A
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solution
nevirapine
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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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

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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)

Abstract

The present invention provides a kind of preparation method of nevirapine sustained release preparation, the steps include: to be dissolved in nevirapine 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 nevirapine 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 nevirapine 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 nevirapine sustained release preparations Preparation method.
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.
Nevirapine is the non-nucleoside reverse transcriptase inhibitor of HIV-1, and the reverse transcriptase of nevirapine and HIV-1 are direct It connects and blocks the DNA polymerase activity that RNA is relied on and DNA is relied on by rupturing the catalysis end of this enzyme.Nevirapine Treatment H IV -1 is shared with other antiretroviral drugs to infect.For the pregnant of antiretroviral treatment is not used when childbirth Woman can prevent the mother-to-baby transmission of H IV -1 using nevirapine.It is permanent at a predetermined rate after the administration of nevirapine oral slow-releasing preparation Determine slow release, it can rapid delivery of pharmaceuticals rather than conventional formulation.With corresponding ordinary preparation, such as fast-release tablet, capsule, oral solution It compares, the compliance of patient can be improved and increases curative effect of medication.The major advantage of sustained release preparation is can to reduce dosage frequency And avoid taking the blood concentration peak valley phenomenon of ordinary preparation appearance.Sustained release preparation can be kept within the relatively long time Blood concentration is stablized within the scope of effective blood drug concentration, to improve Drug safety.Nevirapine sustained release preparation master at present It to use skeleton agent technology to produce, commonly use ethyl cellulose, acrylic resin, lactose, the auxiliary materials such as microcrystalline cellulose.But with such The risk that drug release changes during the dosage form of technology production has burst release and storage, and supplementary product consumption is big, is unfavorable for taking orally.It is right This provides a kind of safe and effective, reliable in quality, high production efficiency for clinic, and supplementary product consumption is moderate, the stable Nai Wei of drug release It is necessary to even up sustained release preparation, 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 nevirapine 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 nevirapine sustained release preparation, which is characterized in that the sustained release preparation by nevirapine, hydroxypropylβ-cyclodextrin, Polylactic acid, mannitol, polyethylene glycol 200,95% ethyl alcohol and acetone composition.The nevirapine sustained release preparation each component is by weight Amount containing 95% ethyl alcohol 150~170, contains hydroxypropylβ-cyclodextrin 100~130, contains mannitol 20~30 than containing nevirapine 100, Containing acetone 100~140, contain polylactic acid 100~140, contain polyethylene glycol 200 20~40, the polylactic acid relative molecular weight is 5000~20000.
It is a further object to provide a kind of methods for being prepared into nevirapine sustained release preparation, which is characterized in that The specific steps of this method are as follows:
1) nevirapine is dissolved in 95% ethyl alcohol, obtains Nevirapine, be 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 nevirapine sustained release preparation with low temperature spray drying legal system.
Nevirapine sustained release preparation of the invention is passed through to be released with the cumulative in vitro of commercially available same dosage form nevirapine sustained release preparation Dose comparative study, it was demonstrated that nevirapine sustained release preparation drug release of the invention is more stable, and slow-release function is more preferable.And it is prepared Method high production efficiency, capsule material dosage is moderate, and dry materials temperature is low, and obtained carrying medicine is uniform in size, and encapsulation rate is greater than 80%, 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 nevirapine sustained release preparation.In Fig. 1, abscissa is time (hour), and ordinate is 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 nevirapine sustained release preparation.In Fig. 2, abscissa is time (hour), and ordinate is 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 nevirapine sustained release preparation.In Fig. 3, abscissa is time (hour), and ordinate is 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 nevirapine sustained release preparation.
Embodiment one:
1) 100g nevirapine is dissolved in 150g95% ethyl alcohol, obtains nevirapine ethanol solution, is denoted as solution A；
2) 100g hydroxypropylβ-cyclodextrin and 20g mannitol are added in solution A, obtains solution B；
3) 100g polylactic acid and 20g polyethylene glycol 200 are dissolved in 100g 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 nevirapine sustained release preparation, the temperature of spray drying with low temperature spray drying legal system Degree control is 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 80.53% that gained sample, which measures encapsulation rate, carrying drug ratio 50.57%, body Outer release experiment proves that this preparation energy slow release nevirapine, nevirapine are finally discharged up to 90% or more, sees Fig. 1.
Embodiment two:
1) 100g nevirapine is dissolved in 160g95% ethyl alcohol, obtains nevirapine ethanol solution, is denoted as solution A；
2) 120g hydroxypropylβ-cyclodextrin and 25g mannitol are added in solution A, obtains solution B；
3) 130g polylactic acid and 30g polyethylene glycol 200 are dissolved in 130g 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 nevirapine sustained release preparation, the temperature of spray drying with low temperature spray drying legal system Degree control is 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 80.79% that gained sample, which measures encapsulation rate, carrying drug ratio 50.16%, body Outer release experiment proves that this preparation energy slow release nevirapine, nevirapine are finally discharged up to 90% or more, sees Fig. 2.
Embodiment three:
1) 100g nevirapine is dissolved in 170g95% ethyl alcohol, obtains nevirapine ethanol solution, is denoted as solution A；
2) 130g hydroxypropylβ-cyclodextrin and 30g mannitol are added in solution A, obtains solution B；
3) 140g polylactic acid and 40g polyethylene glycol 200 are dissolved in 140g 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 nevirapine 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 81.06% that gained sample, which measures encapsulation rate, carrying drug ratio 51.28%, body Outer release experiment proves that this preparation energy slow release nevirapine, nevirapine are finally discharged up to 90% or more, sees 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 nevirapine sustained release preparation, it is characterised in that the nevirapine sustained release preparation is by Nai Weila Flat, hydroxypropylβ-cyclodextrin, polylactic acid, mannitol, polyethylene glycol 200,95% ethyl alcohol, acetone composition.
2. the preparation method of nevirapine sustained release preparation as described in claim 1, it is characterised in that the steps include:
1) nevirapine is dissolved in 95% ethyl alcohol, obtains Nevirapine, be 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 nevirapine sustained release preparation with low temperature spray drying legal system.
3. nevirapine sustained release preparation each component as claimed in claim 1 or 2 contains nevirapine 100 by weight, contain 95% Ethyl alcohol 150~170 contains hydroxypropylβ-cyclodextrin 100~130, contains mannitol 20~30, contains acetone 100~140, contains polylactic acid 100~140, contain polyethylene glycol 200 20~40.
4. the preparation method of nevirapine sustained release preparation as claimed in claim 1 or 2, it is characterised in that opposite point of polylactic acid Son amount is 5000~20000.
5. the preparation method of nevirapine sustained release preparation as claimed in claim 3, it is characterised in that the temperature of low temperature spray drying Degree is 55 DEG C~60 DEG C, and nozzle diameter is 0.5mm~1mm, and hothouse vacuum degree is 0.03MPA~0.04MPA, solution D flow It is 500ml/ hours~1000ml/ hours.
CN201711109748.5A 2017-11-11 2017-11-11 A kind of preparation method of nevirapine sustained release preparation Withdrawn CN108992424A (en)

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