CN103860499A - Methadone hydrochloride orally disintegrating tablet and preparation method thereof - Google Patents
Methadone hydrochloride orally disintegrating tablet and preparation method thereof Download PDFInfo
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- CN103860499A CN103860499A CN201410113511.4A CN201410113511A CN103860499A CN 103860499 A CN103860499 A CN 103860499A CN 201410113511 A CN201410113511 A CN 201410113511A CN 103860499 A CN103860499 A CN 103860499A
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- oral cavity
- cavity disintegration
- disintegration tablet
- methadone hydrochloride
- diluent
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Abstract
The invention belongs to the technical field of pharmacy, and particularly discloses an orally disintegrating tablet taking methadone hydrochloride as an active ingredient, serving as a surgical anesthetic medicine and capable of relieving pain of patients, and a preparation method of the orally disintegrating tablet. The methadone hydrochloride orally disintegrating tablet consists of the following components in parts by weight: 0.5-1.0 part of methadone hydrochloride, 30-100 parts of diluent, 0.5-10 parts of disintegrating agent, 0.1-0.5 part of lubricant, 0.01-0.1 part of flavoring agent and 0.01-0.03 part of binding agent, wherein the diluent is a combination of chitosan and one or two selected from lactose and mannitol. The moisture resistance of the prepared orally disintegrating tablet prepared by the application is obviously improved; the tablet is favorable for improving the stability of the preparation and guaranteeing the quality in production and storage processes.
Description
Invention field
The present invention relates to chemical pharmacy field, be specifically related to surgery anesthesia medication, for the pharmaceutical preparation of reduction of patient pain, i.e. a kind of methadone hydrochloride oral cavity disintegration tablet and preparation method thereof.
Background of invention
Methadone hydrochloride is opioid receptor agonist, and Main Function is in receptor.Its pharmacological action is similar to morphine, and the analgesic efficacy and persistent period are also suitable with morphine, can be used for anesthesia in operating room medication, or reduction of patient pain.Methadone hydrochloride also can produce the effect of respiration inhibition, antitussive, cooling, myosis, sedation a little less than, but repeat administration still can cause obvious sedation.Its feature is oral effective, and the action period of inhibition morphine addiction person's withdrawal symptom is long, and repeat administration is still effective.Toleration and addiction occur slower, and withdrawal symptom is slightly light, but withdrawal is more difficult.
In prior art, the domestic report there are no the slow releasing tablet about making take methadone hydrochloride as raw material, abroad only the U.S. has commodity by name
the report of (Dispersible Tablets CII, USP, 2007), but do not report prescription component (consumption proportion) and preparation method thereof.In prior art, the domestic report there are no the dispersible tablet about making take methadone hydrochloride as raw material, abroad only the U.S. has commodity by name
the report of (Dispersible Tablets CII, USP, 2007), but do not report prescription component (consumption proportion) and preparation method thereof.
The methadone hydrochloride preparation having gone on the market abroad is at present conventional tablet and oral liquid.And oral cavity disintegration tablet can not need water or only need use a small amount of water, without chewing, tablet is placed in lingual surface, meets after the rapid disintegrate of saliva, borrows and swallows power, and medicine can absorb rapidly onset.Compared with conventional tablet, oral cavity disintegration tablet has the following advantages: 1. absorption is fast, bioavailability is high.2. taking convenience: oral cavity disintegration tablet needn't be used water delivery service, and saliva can make its disintegrate or dissolving, can swallow by common dose, can be placed in water and takes after disintegrate again, can also not need to take medicine with water swallow.Be particularly useful for being badly in need of lenitive patient.3. intestinal is residual few, and the low medicine of side effect arrives the gastrointestinal tract rapid disintegrate of energy before and is dispersed into trickle granule, causes medicine to distribute in gastrointestinal tract large area, and absorption point increases, thereby has reduced medicine to gastrointestinal local excitation.4. avoid the first pass effect of liver: due to oral cavity disintegration tablet rapidly disintegrate in mouth, except major part enters gastrointestinal tract with swallowing act, also have considerable part direct oral cavity to absorb, thereby rapid-action, first pass effect is little.
Oral cavity disintegration tablet refers to not to be needed water or only needs a small amount of water, and without chewing, tablet is placed in lingual surface, and chance saliva is collapsed rapidly broken, and reflexive enters in body with swallowing act.Be characterized in that absorption is fast, bioavailability is high, intestinal is residual few, taking convenience.Oral cavity disintegration tablet needn't be used water delivery service, and saliva can make its disintegrate, for dysphagia, the inconvenient person that fetches water take medicine convenience is provided.Due to oral cavity disintegration tablet, it is absorbing environmental or air moisture very easily, once and use before absorb a small amount of moisture can cause the quality of tablet to change, affect its clinical use.Therefore the production to preparation and packaging process have proposed strict requirement, change if control the bad quality that will cause oral cavity disintegration tablet.
Summary of the invention
The invention provides a kind of new methadone hydrochloride disintegrating tablet and preparation method thereof, significantly reduction of patient pain, for anesthetic action, its processing technology is simple, and the quality of the pharmaceutical preparations is reliable and stable, has solved conventional oral cavity disintegration tablet technique hygroscopicity problem.
On the one hand, the invention provides a kind of methadone hydrochloride oral cavity disintegration tablet, wherein, the weight portion of described oral cavity disintegration tablet consists of:
Methadone hydrochloride 0.5-1.0 part
Diluent 30-100 part
Disintegrating agent 0.5-10 part
Lubricant 0.1-0.5 part
Correctives accounts for 0.01-0.1 part
Binding agent 0.01-0.03 part,
Wherein diluent be chitosan and with the compositionss of one or both common compositions that are selected from lactose, mannitol, the part by weight of chitosan in diluent is 20%-50%.
Some embodiments therein, oral cavity disintegration tablet of the present invention, the part by weight of wherein said chitosan in diluent is 50%.
Some embodiments therein, oral cavity disintegration tablet of the present invention, wherein said disintegrating agent is a kind of or its combination in low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium.
Some embodiments therein, oral cavity disintegration tablet of the present invention, wherein said lubricant is magnesium stearate or sodium lauryl sulphate.
Some embodiments therein, oral cavity disintegration tablet of the present invention, wherein said binding agent is PVP K30.
Some embodiments therein, oral cavity disintegration tablet of the present invention, wherein said taste masking is selected from a kind of or its combination in Aspartame, Mint Essence.
Some embodiments therein, oral cavity disintegration tablet of the present invention, wherein, the weight portion of described oral cavity disintegration tablet consists of:
Methadone hydrochloride 5g
Mannitol 50g
Chitosan 50g
Low-substituted hydroxypropyl cellulose 10g
Magnesium stearate 5g
Aspartame 0.5g
PVP K30 0.3g
Make 1000.
On the other hand, the present invention relates to a kind of preparation method of oral cavity disintegration tablet of the present invention, it comprises following steps: (1) gets methadone hydrochloride and diluent, disintegrating agent by prescription, and mix homogeneously, obtains mixture; (2) get PVP K30, be dissolved in alcoholic solution, make the alcoholic solution containing 2% PVP K30; (3) in the mixture of step 1, add the alcoholic solution of the PVP K30 of 2% concentration, cross 20 mesh sieve granule processed, 40 ℃-60 ℃ be dried after, 16 mesh sieve granulate; (4) in the granule after granulate, add lubricant, correctives, tabletting, to obtain final product.
The present invention is by the suitability research to methadone hydrochloride and pharmaceutic adjuvant, find by selecting specific pharmaceutic adjuvant composition through experiment, can improve greatly the easy hygroscopicity of oral cavity disintegration tablet, improve quality stability in preparation production and storage process, and the disintegrate effect of oral cavity disintegration tablet is unaffected, wherein in diluent, chitosan is essential component.The present invention surprisingly finds that by lot of experiments the diluent of methadone hydrochloride oral cavity disintegration tablet is chitosan and when being selected from compositionss of one or both common compositions of lactose, mannitol, its moisture resistance significantly improves, and is conducive to improve the stability of preparation and guarantees to produce the quality in storage process.
Excipient of the present invention comprises, but be not limited to, ion-exchanger, aluminum, aluminium stearate, lecithin, serum albumin, as human albumin, buffer substance is as phosphate, glycine, sorbic acid, potassium sorbate, the partial glycerol ester admixture of saturated vegetable fatty acid, water, salt or electrolyte, as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloid silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanoline, sugar, as lactose, dextrose plus saccharose, starch is as corn starch and potato starch, the derivant of cellulose and it is as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, natural gum powder, Fructus Hordei Germinatus, gelatin, Pulvis Talci, adjuvant is as cocoa butter and suppository wax, oily as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines, glycols compound, as propylene glycol and Polyethylene Glycol, esters is as ethyl oleate and ethyl laurate, agar, buffer agent is as magnesium hydroxide and aluminium hydroxide, alginic acid, pyrogen-free water, Deng oozing salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating dress material, sweeting agent, flavoring agent and spice, antiseptic and antioxidant.
Pharmaceutical composition of the present invention can also optionally contain one or more diluent.The example of diluent comprises mannitol, sorbitol, biphosphate calcium dihydrate, microcrystalline Cellulose and efflorescence cellulose.Preferred diluent is microcrystalline Cellulose.Microcrystalline Cellulose can be obtained from several suppliers, comprises Avicel PH101, Avicel PH102, Avicel PH103, AvicelPH105 and Avicel PH200 that FMCCorporation manufactures.
Pharmaceutical composition of the present invention can also optionally contain disintegrating agent.Disintegrating agent can be the one in several modified starches, modified cellulose polymer or polycarboxylic acids, such as crosslinked Carboxymethyl cellulose sodium, Explotab, polacrilin potassium and calcium carboxymethylcellulose (CMCCalcium).In one embodiment, disintegrating agent is croscarmellose sodium.Croscarmellose sodium NF type A obtains with trade name " Ac-di-sol " on market.
Pharmaceutical composition of the present invention can also optionally contain one or more surfactants or wetting agent.Surfactant can be anion, cation or neutral surface active agent.Anion surfactant comprises sodium lauryl sulfate, dodecyl sodium sulfate, oleyl sodium sulfate and the sodium laurate mixing with stearate and Talcum.Cationic surfactant comprises benzalkonium chloride and alkyl trimethyl ammonium bromide.Neutral surface active agent comprises glycerol list olein, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and anhydro sorbitol fat.The embodiment of wetting agent comprises poloxamer, polyoxyethylene alkyl ether, castor oil derivatives and polyoxyethylene 8 stearate fat.
The present invention can also optionally join antioxidant in preparation, thereby gives its chemical stability.Antioxidant is selected from the extract of a-tocopherol, Y-tocopherol, S-tocopherol, tocopherol enrichment natural origin, sodium or calcium salt, the Vitamin C acyl cetylate of L-AA and it, amass wealth by heavy taxation propyl propionate, amass wealth by heavy taxation misery ester, amass wealth by heavy taxation sour dodecyl ester, Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA).In one embodiment, antioxidant is BHT or BHA.
The preferred dosage form of drug composition of the present invention is the tablet of preparing by compression method.Described tablet can carry out film with the mixture such as hydroxypropyl cellulose and hydroxypropyl emthylcellulose, contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian in this mixture; The mixture of polyvinyl alcohol (PVA) and Polyethylene Glycol (PEG), contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian; Or any other suitable instant-free coating agent.Coating provides taste masked and other stability to final tablet.What commercially available film provided for Colorcon is preparation mixture of powders
The present invention can also add sweeting agent and/or fumet.
The specific embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
Embodiment 1
Preparation prescription is:
Methadone hydrochloride 5g
Mannitol 50g
Chitosan 50g
Low-substituted hydroxypropyl cellulose 10g
Magnesium stearate 5g
Aspartame 0.5g
PVP K30 0.3g
Make 1000.
Embodiment 2
Preparation prescription is:
Methadone hydrochloride 5g
Lactose 80g
Chitosan 16g
Cross-linking sodium carboxymethyl cellulose 5g
Magnesium stearate 1.2g
Mint Essence 0.6g
PVP K30 0.2g
Make 1000.
Embodiment 3
Preparation prescription is:
Methadone hydrochloride 5g
Mannitol 25g
Lactose 25g
Chitosan 50g
Crosslinked polyethylene pyrroles protective embankment ketone 10g
Sodium lauryl sulphate 2g
Aspartame 1.6g
Mint Essence 0.4g
PVP K30 0.2g
Make 1000.
Embodiment 4
Preparation prescription is:
Methadone hydrochloride 5g
Lactose 60g
Chitosan 40g
Crosslinked carboxymethyl fecula sodium 6g
12 protective embankment base sodium sulfate 1g
Aspartame 0.4g
Mint Essence 0.6g
PVP K30 0.1g
Make 1000.
Embodiment 5
Preparation prescription is:
Methadone hydrochloride 5g
Mannitol 75g
Chitosan 25g
Low-substituted hydroxypropyl cellulose 10g
Magnesium stearate 1.2g
Aspartame 0.6g
PVP K30 0.1g
Make 1000.
Embodiment 6
Preparation prescription is:
Methadone hydrochloride 5g
Mannitol 50g
Chitosan 50g
Crosslinked carboxymethyl fecula sodium 5g
Low-substituted hydroxypropyl cellulose 3g
Sodium lauryl sulphate 1g
Aspartame 0.4g
Mint Essence 0.2g
PVP K30 0.2g
Make 1000.
Embodiment 7
Preparation prescription is:
Methadone hydrochloride 5g
Lactose 30g
Mannitol 20g
Chitosan 50g,
Cross-linking sodium carboxymethyl cellulose 5g
Magnesium stearate 1g
Aspartame 1.0g
PVP K30 0.3g
Make 1000.
Embodiment 8
Preparation prescription is:
Methadone hydrochloride 5g,
Mannitol 100g,
Cross-linking sodium carboxymethyl cellulose 5g,
12 protective embankment base sodium sulfate 1g,
Aspartame 0.4g,
Mint Essence 0.2g
PVP K30 0.3g
Make 1000.
Embodiment 9
Preparation prescription is:
Methadone hydrochloride 3g
Lactose 100g
Crospolyvinylpyrrolidone 3g,
12 protective embankment base sodium sulfate 1g
Aspartame 0.3g
Mint Essence 0.4g
PVP K30 0.3g
Make 1000.
The preparation technology of above embodiment and comparing embodiment is:
1. get methadone hydrochloride and diluent, disintegrating agent by prescription, mix homogeneously, obtains mixture;
2. get PVP K30, be dissolved in alcoholic solution, make the alcoholic solution containing 2% PVP K30;
3. in the mixture of step 1, add the alcoholic solution of the PVP K30 of 2% concentration, cross 20 mesh sieve granule processed, 40 ℃-60 ℃ be dried after, 16 mesh sieve granulate;
4. in the granule after granulate, add lubricant, correctives, tabletting, to obtain final product.
Biological activity test
Disintegration is measured: measure respectively oral cavity disintegration tablet prepared by above-described embodiment disintegration time in disintegration tester, measure oral cavity disintegration tablet disintegration in vivo by volunteer simultaneously.
The external disintegration time of the oral cavity disintegration tablet of above-described embodiment is 6-15 second, average disintegration time 10.5 seconds.
The disintegration time of the oral cavity disintegration tablet of above-described embodiment in oral cavity is 13-17 second, and average disintegration time 15.2 seconds, meets the requirement of oral cavity disintegration tablet.
The Orally disintegrating tablet recipe of embodiment 8,9 does not add chitosan, and its external disintegration time is respectively 19,20 seconds, and the disintegration time in oral cavity is respectively 23,25 seconds
Moisture resistance is measured: measure in the 5th day and the oral cavity disintegration tablet for preparing for the 10th day hygroscopicity under super-humid conditions according to preceding method, its 5th day rate of body weight gain is 2.0%-3.8%, and average growth rate is 2.5%; Within the 10th day, rate of body weight gain is 6.8-8.5%, and average growth rate is 7.4%, more consistent with preliminary experimental results.The 5th day rate of body weight gain of the oral cavity disintegration tablet of embodiment 8,9 is respectively 9.7%, 11.9%, the 10 day rate of body weight gain is respectively 19.4%, 21.6%.
Further long-time stability experiment shows the raising due to humidity-proof ability of oral cavity disintegration tablet that the present invention prepares, store after 24 months product basicly stable, and embodiment 8,9 oral cavity disintegration tablets after 18 months character just there is change, the content of its active constituents of medicine also declines obviously.
Claims (8)
1. a methadone hydrochloride oral cavity disintegration tablet, wherein, the weight portion of described oral cavity disintegration tablet consists of:
Methadone hydrochloride 0.5-1.0 part
Diluent 30-100 part
Disintegrating agent 0.5-10 part
Lubricant 0.1-0.5 part
Correctives accounts for 0.01-0.1 part
Binding agent 0.01-0.03 part,
Wherein diluent be chitosan and with the combinations of one or both common compositions that are selected from lactose, mannitol
Thing, the part by weight of chitosan in diluent is 20%-50%.
2. oral cavity disintegration tablet according to claim 1, the part by weight of wherein said chitosan in diluent is 50%.
3. oral cavity disintegration tablet according to claim 1, wherein said disintegrating agent is a kind of or its combination in low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium.
4. oral cavity disintegration tablet according to claim 1, wherein said lubricant is magnesium stearate or sodium lauryl sulphate.
5. oral cavity disintegration tablet according to claim 1, wherein said binding agent is PVP K30.
6. oral cavity disintegration tablet according to claim 1, wherein said taste masking is selected from a kind of or its combination in Aspartame, Mint Essence.
7. according to the oral cavity disintegration tablet described in claim 1-6 any one, wherein, the weight portion of described oral cavity disintegration tablet consists of:
Methadone hydrochloride 5g
Mannitol 50g
Chitosan 50g
Low-substituted hydroxypropyl cellulose 10g
Magnesium stearate 5g
Aspartame 0.5g
PVP K30 0.3g
Make 1000.
8. a preparation method for the oral cavity disintegration tablet described in claim 1-7 any one, it comprises following steps: (1) gets methadone hydrochloride and diluent, disintegrating agent by prescription, and mix homogeneously, obtains mixture; (2) get PVP K30, be dissolved in alcoholic solution, make the alcoholic solution containing 2% PVP K30; (3) in the mixture of step 1, add the alcoholic solution of the PVP K30 of 2% concentration, cross 20 mesh sieve granule processed, 40 ℃-60 ℃ be dried after, 16 mesh sieve granulate; (4) in the granule after granulate, add lubricant, correctives, tabletting, to obtain final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410113511.4A CN103860499A (en) | 2014-03-25 | 2014-03-25 | Methadone hydrochloride orally disintegrating tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410113511.4A CN103860499A (en) | 2014-03-25 | 2014-03-25 | Methadone hydrochloride orally disintegrating tablet and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105476968A (en) * | 2015-12-18 | 2016-04-13 | 北京万全德众医药生物技术有限公司 | Raloxifene hydrochloride orally disintegrating tablet and preparation method thereof |
| WO2021028640A1 (en) * | 2019-08-13 | 2021-02-18 | Ethypharm | Low-dosage orodispersible opioid tablet and method for preparing same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101683324A (en) * | 2008-09-27 | 2010-03-31 | 张晓芳 | Oral disintegrative tablet of sildenafil citrate and preparation method thereof |
| CN101843596A (en) * | 2010-03-26 | 2010-09-29 | 中国人民解放军广州疗养院 | Methadone hydrochloride dispersible tablet and preparation method thereof |
-
2014
- 2014-03-25 CN CN201410113511.4A patent/CN103860499A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101683324A (en) * | 2008-09-27 | 2010-03-31 | 张晓芳 | Oral disintegrative tablet of sildenafil citrate and preparation method thereof |
| CN101843596A (en) * | 2010-03-26 | 2010-09-29 | 中国人民解放军广州疗养院 | Methadone hydrochloride dispersible tablet and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105476968A (en) * | 2015-12-18 | 2016-04-13 | 北京万全德众医药生物技术有限公司 | Raloxifene hydrochloride orally disintegrating tablet and preparation method thereof |
| WO2021028640A1 (en) * | 2019-08-13 | 2021-02-18 | Ethypharm | Low-dosage orodispersible opioid tablet and method for preparing same |
| FR3099881A1 (en) * | 2019-08-13 | 2021-02-19 | Ethypharm Sa | Low strength opioid orodispersible tablet and its preparation method. |
| CN114258300A (en) * | 2019-08-13 | 2022-03-29 | 埃迪制药公司 | Low dose orodispersible opioid tablet and method of making same |
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Application publication date: 20140618 |