CN103070840A - Oxycodone hydrochloride slow release dripping pills and preparation method thereof - Google Patents

Oxycodone hydrochloride slow release dripping pills and preparation method thereof Download PDF

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Publication number
CN103070840A
CN103070840A CN 201210438212 CN201210438212A CN103070840A CN 103070840 A CN103070840 A CN 103070840A CN 201210438212 CN201210438212 CN 201210438212 CN 201210438212 A CN201210438212 A CN 201210438212A CN 103070840 A CN103070840 A CN 103070840A
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CN
China
Prior art keywords
oxycodone hydrochloride
preparation
framework material
pill
substrate
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN 201210438212
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Chinese (zh)
Inventor
曲韵智
王金
强振君
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Beijing Chia Tai Green Continent Pharmaceutical Co Ltd
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Beijing Chia Tai Green Continent Pharmaceutical Co Ltd
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Application filed by Beijing Chia Tai Green Continent Pharmaceutical Co Ltd filed Critical Beijing Chia Tai Green Continent Pharmaceutical Co Ltd
Priority to CN 201210438212 priority Critical patent/CN103070840A/en
Publication of CN103070840A publication Critical patent/CN103070840A/en
Pending legal-status Critical Current

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Abstract

The invention relates to the oxycodone hydrochloride slow release dripping pills and a preparation method, and relates to a medicine oxycodone hydrochloride sustained release preparation which can alleviate moderate pain and severe pain and a preparation method thereof. According to the invention, a solid dispersion technology is employed to prepare the slow release dripping pills, the slow release dripping pills are used for solving the disadvantages of low biological availability of oral preparations, and the invention provides the slow release dripping pills with the characteristics of high bioavailability, rapid effect, less administration frequency, convenient administration, less toxic and side effect, convenient storage and transportation and oral administration and the preparation method.

Description

Oxycodone hydrochloride sustained-release dropping pill and preparation method thereof
Technical field
The present invention relates to a kind of moderate of alleviating to medicine oxycodone hydrochloride slow releasing preparation of severe pain and preparation method thereof.
Background technology
Oxycodone hydrochloride is the opioid compounds of a kind of C18H21NO4HCl of containing, and molecular weight is 351.83, and its chemistry is by name: 4,5-epoxy radicals-14-hydroxy-3-methoxy-17-methylmorphine alkane-6-keto hydrochloride.
The crystalline powder that white is tasteless
Oxycodone hydrochloride (oxycodone hydrochloride) is the semi-synthetic analgesic of potent opiates by the exploitation of U.S. Lehigh Valley Technologies company, in the new drug approval of on October 20th, 2010 by U.S. FDA, be used for alleviating the lasting moderate of human body to severe pain.Oxycodone hydrochloride belongs to the semi-synthetic derivant of morphine, its Analgesic Mechanism is more special, not only act on the μ-opiate receptor in the central nervous system, can also act on κ-opiate receptor under some condition, this medicine is weaker than morphine and methadone to the affinity of μ-opiate receptor in vivo, but its active metabolite oxymophone has stronger affinity to μ-opiate receptor.Alleviation experiment for the tumor patient myalgia shows that total analgesic effect that oxymophone produces is 8-7 times of morphine, and the peak value analgesic effect is 13 times of morphine.In addition, compare with morphine, oxycodone hydrochloride also has higher oral administration biaavailability.
Oxycodone hydrochloride is as a generic drugs thing, now existing many pharmacy corporations are classified II class controlled drug (schedule II controlledsubstance) because it has potential abuse risk by U.S. DEA and FDA with different trade names and dosage form listing.Luxembourg Euro-Celtique company obtains United States Patent (USP) mandate (us5508042) on April 16th, 1996, for the protection of composition and the preparation method of OxyContin.The human hot melt extruded legal systems such as McGinity JW in Texas university Austin branch school obtained United States Patent (USP) mandate (us6488963) for a kind of non-film controlled release preparation of oxycodone hydrochloride on the 3rd in December in 2002.U.S. Purdue Pharma company is respectively at obtaining United States Patent (USP) mandate (us7674799, us7674800, us7683072) on March 9th, 2010 and 23 days, and these three patents have been carried out corresponding protection to the composition of synthesis technique, its slow releasing tablet and the capsule of oxycodone hydrochloride and preparation method etc.In addition, in order to prevent that medicine from being abused, a kind of Tablet and Capsula agent that can prevent from artificially extracting the oxycodone hydrochloride composition has been invented by German Grunenthal Gm bH company, and obtains United States Patent (USP) mandate (us7776314) on August 17th, 2010.
The oxycodone hydrochloride oral formulations that utilizes prior art to obtain, domestic production the plain pharmacy conventional tablet of Beijing China arranged, the import medicine has Beijing to sprout slow releasing tablet and two of the controlled release tablets that base of a fruit pharmaceutical Co. Ltd produces to produce official written reply.And in the clinical practice, the patient tends to use Beijing to sprout the import drugs of base of a fruit pharmaceutical Co. Ltd packing, and it is about more than 90% to account for the market share, and the import drug price is high, increase patient's financial burden, and domestic dosage form of the same race has almost identical result of use.Simultaneously, owing to reasons such as technologies of preparing, exist after the Tablet and Capsula agent is taken that dissolve scattered time limit is long, dissolution is low, absorb the problems such as relatively poor, liver sausage first pass effect and bioavailability are lower, thereby affect the performance of drug effect, also directly affect the effect for the treatment of.
Summary of the invention
The object of the invention is to solve the deficiency of above-mentioned preparation, a kind of bioavailability height that has is provided, prove effective rapidly, long action time, medicining times is few, taking convenience, toxicity, side effect is few, is convenient to store and transportation, but oxycodone hydrochloride sustained-release dropping pill of oral medication and preparation method thereof.
Oxycodone hydrochloride sustained-release dropping pill involved in the present invention take oxycodone hydrochloride as raw material, is prepared from the pharmaceutically suitable carrier as substrate.Be prepared by the following technical solutions, can obtain oxycodone hydrochloride sustained-release dropping pill involved in the present invention:
[preparation method]
1. write out a prescription
1.1 raw material: oxycodone hydrochloride
1.1.1 chemical name: 4,5-epoxy radicals-14-hydroxy-3-methoxy-17-methylmorphine alkane-6-keto hydrochloride
1.1.2 Chinese phonetic alphabet name: yansuanqiangkaotong huanshi diwan
1.2 substrate: comprise hydrophilic framework material and hydrophobicity framework material
1.2.1 hydrophilic framework material: mixed by two or three in Macrogol 4000, polyethylene glycol 6000, PEG20000, the carboxymethyl starch sodium.
1.2.2 hydrophobicity framework material: by glyceryl monostearate or stearic acid or their compositions of mixtures.
2. component consists of: calculate according to percentage by weight, oxycodone hydrochloride sustained-release dropping pill involved in the present invention is comprised of the substrate of 10-30% oxycodone hydrochloride and 40-90%, and substrate comprises 30-70% hydrophilic framework material and 10-25% hydrophobicity framework material.
3. preparation method: take by weighing first described hydrophilic framework material and hydrophobicity framework material, place to heat in the heating container and stir and make it melting, the oxycodone hydrochloride that adds corresponding proportion, after stirring, use pill dripping machine, under heat-retaining condition, the medicinal liquid of melting or mixing is splashed in the condensation column that fills different temperatures condensed fluid up and down, take out after the molding, and get final product.
4. in the above-mentioned preparation method, the temperature during described heating and melting is 55 ℃~85 ℃.
5. in the above-mentioned preparation method, described condensed fluid is more than or equal to the dimethicone of 100# or liquid paraffin or vegetable oil.
6. in the above-mentioned preparation method, the temperature on described condensed fluid top is 20 ℃~35 ℃, and the temperature of bottom is-4 ℃~10 ℃.
[beneficial effect]
Oxycodone hydrochloride is the semi-synthetic analgesic of potent opiates, tests for the alleviation of tumor patient myalgia to show that total analgesic effect that oxycodone hydrochloride produces is 8-7 times of morphine, and the peak value analgesic effect is 13 times of morphine.The oxycodone hydrochloride oral formulations that utilizes at present prior art to obtain, domestic production the plain pharmacy conventional tablet of Beijing China arranged, the import medicine has Beijing to sprout slow releasing tablet and two of the controlled release tablets that base of a fruit pharmaceutical Co. Ltd produces to produce official written reply.Owing to reasons such as technologies of preparing, exist the problems such as dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, medicining times is many, and blood drug level is not steady, and liver sausage first pass effect and bioavailability are lower after the tablets, thereby affect the performance of drug effect, also directly affect the effect for the treatment of.
The invention provides a kind of bioavailability height that has, prove effective rapidly, long action time, medicining times is few, taking convenience, toxicity, side effect is few, is convenient to store and transportation, but oxycodone hydrochloride sustained-release dropping pill of oral medication and preparation method thereof.
In addition, compare with the administering mode of tablet, capsule, exist essential distinction.Drop pill with the solid dispersion technology preparation can adopt oral and sublingual administration, and effective ingredient is fully contacted with mucomembranous surface, absorbs by mucomembranous epithelial cell, directly enters blood circulation.Especially sublingual administration administration can directly enter blood circulation without gastrointestinal tract and liver, has effectively avoided first pass effect, thus the characteristics such as it is rapid to have an onset, and bioavailability is high, and side effect is little, and medication is convenient.
1. this dropping pill formulation volume is little, lightweight, more is applicable to carry.After containing entrance cavity, contact namely with saliva and to dissolve rapidly, and by buccal absorption, and the impact of not taken food, namely before or after meals all can containing be taken.
The contained drug dose of each drop pill of this preparation accurately, be uniformly dispersed, release slowly, have long-acting, to reduce patient's medication number of times, the patient who is suitable for various disease, the different state of an illness, all ages and classes more flexibly and accurately grasps dosage.
3. the production process equipment for preparing this preparation-sustained-release dropping pill is simple, easy to operate; Operation is few, with short production cycle, automaticity is high, labor intensity is low, production efficiency is high; Workshop without dust, be conducive to labor protection and environmental protection; The preparation drop pill need to adopt high-tech means and equipment, and principal agent is uniformly dispersed in substrate, and dosage is accurate, and the ball method of double differences is different little than tablet; Production cost is lower than with below 50% of kind tablet.
4. this preparation is by after the heating of solid drugs and substrate, being melt into liquid state, splashes into to make in the not miscible condensed fluid.Operation is to carry out under liquid state, and no dust pollution is not subject to the impact of crystal formation, thereby has guaranteed the quality of medicine, has increased stability.
The specific embodiment
Embodiment 1:
In gross weight 100g, take by weighing substrate PEG4000 35%, PEG6000 20%, and PEG10000 20%, stearic acid 10%, glyceryl monostearate 5%, raw material oxycodone hydrochloride 10%; Substrate placed in the heating container heating and stir make it melting, the oxycodone hydrochloride that adds corresponding proportion, after stirring, use pill dripping machine, under heat-retaining condition, the medicinal liquid of melting or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 85 ℃, and the temperature on condensed fluid top is 20 ℃, and the temperature of bottom is-2 ℃; Take out after the molding,
Products obtained therefrom, 2 hours cumulative release percentage rate are 36%-53%, and 6 hours cumulative release percentage rate are 55%-79%, and the cumulative release percentage rate was 81%~100% in 10 hours, and release is qualified, and roundness is better.
Embodiment 2:
In gross weight 100g, take by weighing substrate PEG4000 30%, PEG6000 30%, and PEG10000 10%, stearic acid 5%, stearic acid 10%, raw material oxycodone hydrochloride 15%; Substrate heated in placing heating container and stir make it melting, the oxycodone hydrochloride that adds corresponding proportion, after stirring, use pill dripping machine, under heat-retaining condition, the medicinal liquid of melting or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 90 ℃, and the temperature on condensed fluid top is 15 ℃, and the temperature of bottom is-1 ℃; Take out after the molding,
Products obtained therefrom, 2 hours cumulative release percentage rate are 45%-62%, and 6 hours cumulative release percentage rate are 63%-73%, and the cumulative release percentage rate was 75%-99% in 10 hours, and release is qualified, and roundness is better.
Embodiment 3:
In gross weight 100g, take by weighing substrate PEG4000 35%, PEG6000 25%, carboxymethyl starch sodium 10%, glyceryl monostearate 15%, raw material oxycodone hydrochloride 20%; Substrate heated in placing heating container and stir make it melting, the oxycodone hydrochloride that adds corresponding proportion, after stirring, use pill dripping machine, under heat-retaining condition, the medicinal liquid of melting or mixing is splashed in the condensation column that fills liquid paraffin, wherein, temperature during heating and melting is 80 ℃, and the temperature on condensed fluid top is 10 ℃, and the temperature of bottom is-3 ℃; Take out after the molding,
Products obtained therefrom, 2 hours cumulative release percentage rate are 51%-65%, and 6 hours cumulative release percentage rate are 69%-83%, and the cumulative release percentage rate was 85%-100% in 10 hours, and release is qualified, and roundness is better.
Embodiment 4:
In gross weight 100g, take by weighing substrate PEG6000 40%, PEG10000 20%, stearic acid 10%, glyceryl monostearate 5%, raw material oxycodone hydrochloride 10%; Substrate heated in placing heating container and stir make it melting, the oxycodone hydrochloride that adds corresponding proportion, after stirring, use pill dripping machine, under heat-retaining condition, the medicinal liquid of melting or mixing is splashed in the condensation column that fills liquid paraffin, wherein, temperature during heating and melting is 75 ℃, and the temperature on condensed fluid top is 10 ℃, and the temperature of bottom is 2 ℃; Take out after the molding.
Products obtained therefrom, 2h cumulative release percentage rate is 44%-62%, and 6h cumulative release percentage rate is 65%-88%, and 10h cumulative release percentage rate is 89%-100%, and release is qualified, and roundness is better.
Embodiment 5:
In gross weight 100g, take by weighing substrate PEG4000 15%, PEG6000 35%, and PEG10000 10%, stearic acid 5%, glyceryl monostearate 5%, raw material oxycodone hydrochloride 30%; Substrate heated in placing heating container and stir make it melting, the oxycodone hydrochloride that adds corresponding proportion, after stirring, use pill dripping machine, under heat-retaining condition, the medicinal liquid of melting or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 75 ℃, and the temperature on condensed fluid top is 25 ℃, and the temperature of bottom is 0 ℃; Take out after the molding.
Products obtained therefrom, 2h cumulative release percentage rate is 51%-71%, and 6h cumulative release percentage rate is 73%-82%, and 10h cumulative release percentage rate is 84%-100%, and release is qualified, and roundness is better.

Claims (4)

1. the present invention relates to a kind of moderate of alleviating to medicine oxycodone hydrochloride sustained-release dropping pill of severe pain and preparation method thereof.Take oxycodone hydrochloride as raw material, consist of by certain component, with being prepared from as the hydrophilic framework material of substrate and pharmaceutically suitable carrier of hydrophobicity framework material, it is characterized in that:
1.1 described hydrophilic framework material: mixed by two or three in Macrogol 4000, polyethylene glycol 6000, PEG20000, the carboxymethyl starch sodium;
1.2 described hydrophobicity framework material: by glyceryl monostearate or stearic acid or their compositions of mixtures;
1.3 described component consists of: calculate according to percentage by weight, oxycodone hydrochloride sustained-release dropping pill involved in the present invention is by 10-30%; The substrate of oxycodone hydrochloride and 50-90% forms, and substrate comprises 35-45% hydrophilic framework material and 30-60% hydrophobicity framework material.
2. oxycodone hydrochloride sustained-release dropping pill according to claim 1 is prepared from by following method:
2.1 count by weight percentage, take by weighing first described hydrophilic framework material and hydrophobicity framework material, place to heat in the heating container and stir and make it to dissolve, the oxycodone hydrochloride that adds corresponding proportion, fully stir, use pill dripping machine, under heat-retaining condition, it is for subsequent use to make into fused solution and/or emulsion and/or suspension;
2.2 adjust the temperature control system of pill dripping machine, make the water dropper temperature heating of pill dripping machine and remain on 55 ℃~90 ℃, the condensing agent cooling also remains on-4-10 ℃ bottom temp, and head temperature remains on 10-35 ℃;
Stablize when reaching desired numerical value respectively 2.3 treat the temperature of pill dripping machine, will contain fused solution and/or emulsion and/or the suspension of oxycodone hydrochloride and substrate, place in the water dropper tank of pill dripping machine, splash in the condensing agent, shrink molding, take out after the molding, wipe the condensed fluid on drop pill surface, both.
3. preparation method according to claim 2, it is characterized in that: the temperature during described heating and melting is 55 ℃~85 ℃.
4. preparation method according to claim 2, it is characterized in that: described condensed fluid is greater than 100# dimethicone or liquid paraffin or vegetable oil.
CN 201210438212 2012-10-31 2012-10-31 Oxycodone hydrochloride slow release dripping pills and preparation method thereof Pending CN103070840A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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Application publication date: 20130501