CN102000037A - Sublingual naloxone hydrochloride dripping pill - Google Patents
Sublingual naloxone hydrochloride dripping pill Download PDFInfo
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- CN102000037A CN102000037A CN2009100921829A CN200910092182A CN102000037A CN 102000037 A CN102000037 A CN 102000037A CN 2009100921829 A CN2009100921829 A CN 2009100921829A CN 200910092182 A CN200910092182 A CN 200910092182A CN 102000037 A CN102000037 A CN 102000037A
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- naloxone hydrochloride
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Abstract
The invention belongs to the technical field of preparations, in particular to a novel sublingual naloxone hydrochloride dripping pill. The invention discloses the sublingual naloxone hydrochloride dripping pill as a medicine for treating the diseases of acute alcoholic intoxication, narcotic analgesic acute intoxication, narcotic analgesic addiction, and the like. The sublingual naloxone hydrochloride dripping pill is prepared from naloxone hydrochloride, dripping pill stroma, a disintegrant and a flavoring agent. The sublingual naloxone hydrochloride dripping pill has the advantages of high bioavailability, quick disintegration, quick effect, simple production technology and low cost and is convenient to take and carry.
Description
Technical field
The invention belongs to the preparation technique field, relate to a kind of new naloxone hydrochloride Sublingual drop pill particularly.
Background technology
Naloxone hydrochloride (NaloxoneHydrochliride) is the derivant of Oxymorphone.Abroad in the nineteen sixty synthetic, applying clinical in 1963, domestic in the nineteen eighty-three synthetic, the analgesia medicine poisoned the specificity antagonism.Be the specific antagonists of opiate receptor, can stop and replace combining of opioid and receptor competitively, remove the opioids poisoning symptom.Discovering afterwards; naloxone hydrochloride can reduce the release of generation, microglia activation and the inflammatory mediator of free radical; improve the energy metabolism of neurocyte; reverse calcium ion, excitatory amino acid rising etc. to neural detrimental effect, and may increase the activity of the endogenous brain protection factor and reach neuroprotective.Clinically, disease such as the naloxone hydrochloride preparation is widely used in treating that anesthetis is excessive, alcoholism, shock, cerebral infarction, cardiopulmonary arrest and respiration inhibition, determined curative effect, side effect is seldom.Because naloxone hydrochloride has above-mentioned effect, so the naloxone hydrochloride preparation more and more is subjected to alcoholism patient's favor in recent years.
The liver first-pass effect of naloxone hydrochloride is strong, and oral administration biaavailability is not good, based on injection, also has sublingual tablet in addition on the present market.Drug administration by injection is very inconvenient, and can incur loss through delay golden hour, and the marketed tablet onset is slower, and bioavailability is low, and market feedback is undesirable.Naloxone hydrochloride of the present invention Sublingual drop pill bioavailability height, disintegrate is rapid, steady quality, produce effects is carried taking convenience fast.Preparation process of the present invention is simple, and the workshop is polluted few, and production process is short, and cost is low.
Summary of the invention
The present invention seeks to overcome the defective of prior art, for clinical treatment provides a kind of bioavailability height, disintegrate is rapid, steady quality, quick produce effects, the medicine naloxone hydrochloride Sublingual drop pill and the preparation technology thereof that carry taking convenience.
The invention is characterized in by naloxone hydrochloride and drop pill substrate, disintegrating agent, correctives formulated.Each composition percentage by weight is: naloxone hydrochloride 0.5%-8%, drop pill substrate 50%-90%, disintegrating agent 1%-8%, correctives 0.5%-40%.
The present invention can be achieved through the following technical solutions:
Naloxone hydrochloride 0.5%-8%, drop pill substrate 50%-90%, disintegrating agent 1%-8%, correctives 0.5%-40% mix homogeneously is pulverized, and sieves, put and be heated to fusion in the heater while stirring, stir the dropping preparation method pill, the water dropper temperature is 80-100 ℃, splashes in dimethicone or other drop pill coolants, and coolant temperature is 0-40 ℃, separate drop pill, absorb coolant, drying, promptly.
Utilize the drop pill of method preparation of the present invention, its beneficial effect is:
1. medicine disintegrate, onset speed is fast, the bioavailability height.The naloxone hydrochloride drop pill is to utilize solid dispersion technology, with medicine and the fusion of drop pill substrate Hybrid Heating, under molten condition, by abundant stirring, drug molecule is dispersed in the substrate.After the system of dripping was finished, medicine was scattered in the substrate with molecularity or superfine crystal state, helps absorption of human body, therefore can effectively improve bioavailability of medicament.
2. drug quality good stability.Because mix homogeneously is abundant, and with short production cycle, drug molecule is evenly distributed in preparation, and is little with the air contact area, is difficult for oxidation, hydrolysis, thus guaranteed drug quality.
3. drop pill production technology, equipment are simple, with short production cycle, the production efficiency height, and production cost is low.
4. dust pollution is few in process of production for drop pill, and the infringement that environment is caused is few, helps labor protection, GMP management, environmental conservation.
The specific embodiment
One, supplementary material
The crude drug of naloxone hydrochloride drop pill is a naloxone hydrochloride.
Adjuvant is that drop pill substrate, disintegrating agent, correctives combine.Drop pill substrate is that one or more are used with in polyethylene glycols, poloxamer, polyoxyethylene stearate (40) ester; Disintegrating agent can be with one or more are used with in carboxymethylstach sodium, polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose sodium, the hyprolose; Correctives is selected in mannitol, sorbitol, aspartame, Mentholum, the sucrose one or more for use.
Two, preparation method
Naloxone hydrochloride 0.5%-8%, drop pill substrate 50%-90%, disintegrating agent 1%-8%, correctives 0.5%-40% mix homogeneously is pulverized, and sieves, put and be heated to fusion in the heater while stirring, stir the dropping preparation method pill, the water dropper temperature is 80-100 ℃, splashes in dimethicone or other drop pill coolants, and coolant temperature is 0-40 ℃, separate drop pill, absorb coolant, drying, promptly.
Three, prescription design and screening
Substrate is selected:
By naloxone hydrochloride and different substrates prescription, the matrix formulations design sees Table 1, according to the operation of the preparation method in (specific embodiment), drips the system drop pill, and selecting outward appearance, the heavy coefficient of variation of ball, molten diffusing time, hardness etc. is index.Observe the influence of matrix species and contents level thereof to product involved in the present invention.Extramatrical other components of drop pill are set at naloxone hydrochloride, carboxymethyl starch sodium, sucrose.Result of the test sees Table 2.
The design of table 1 matrix formulations
Table 2 different substrates each parametric measurement of filling a prescription
| The experiment number | Content | Outward appearance | The heavy coefficient of variation/the % of ball | Hardness | Molten diffusing time/sec |
| 1 | 50％ | Relatively poor | 10.89 | +++ | 193 |
| 2 | 75％ | Generally | 8.36 | +++ | 204 |
| 3 | 90％ | Generally | 8.15 | +++ | 232 |
| 4 | 50％ | Well | 6.72 | ++ | 170 |
| 5 | 75％ | Outstanding | 4.87 | +++ | 176 |
| 6 | 90％ | Outstanding | 4.05 | +++ | 189 |
| 7 | 50％ | Can not be shaped | - | - | - |
| 8 | 75％ | Generally | 4.65 | +++ | 213 |
| 9 | 90％ | Can't drip system | - | - | - |
| 10 | 50％ | Can not be shaped | - | - | - |
| 11 | 75％ | Relatively poor | 12.01 | + | 136 |
| 12 | 90％ | Can't drip system | - | - | - |
| 13 | 50％ | Relatively poor | 9.55 | ++ | 173 |
| 14 | 75％ | Generally | 6.42 | ++ | 179 |
| 15 | 90％ | Can't drip system | - | - | - |
| 16 | 75％ | Outstanding | 3.92 | ++ | 162 |
| 17 | 75％ | Well | 4.06 | ++ | 159 |
| 18 | 75％ | Well | 4.43 | +++ | 187 |
| 19 | 75％ | Well | 4.68 | +++ | 198 |
| 20 | 90％ | Well | 4.92 | +++ | 213 |
| 21 | 75％ | Generally | 5.22 | ++ | 172 |
| 22 | 75％ | Well | 4.81 | +++ | 180 |
| 23 | 75％ | Well | 5.06 | +++ | 197 |
| 24 | 50％ | Generally | 5.22 | ++ | 169 |
Is the best by above experimental result when the ratio of drop pill substrate is with 75% left and right sides as can be seen, and along with the increase of substrate ratio, disintegration time has the trend of prolongation, can occur dripping the phenomenon of system difficulty in addition for the big substrate of viscosity, as cetomacrogol 1000 0; If reduce the substrate ratio then disintegration time reduces, degraded appearance is until can not molding.As use a kind of substrate, be best with the polyethylene glycol 6000; And the mixing disintegrating agent effect of utilizing the substrate physicochemical property to be made into is better.
Disintegrating agent is selected:
By naloxone hydrochloride and different disintegrating agent prescriptions (seeing Table 3), according to the operation of the preparation method in (specific embodiment), drip the system drop pill, select the molten diffusing time as investigating index.Observe the influence of disintegrating agent kind and contents level thereof to product involved in the present invention.Other outer components of drop pill disintegrating agent are set at naloxone hydrochloride, polyethylene glycol 6000, sucrose.Result of the test sees Table 4.
Table 3 disintegrating agent recipe design
The different disintegrating agent disintegrate of table 4 effect test
| The experiment number | Disintegrant content | Disintegration time |
| 1 | 1％ | 236 |
| 2 | 4％ | 183 |
| 3 | 8％ | 174 |
| 4 | 1％ | 209 |
| 5 | 4％ | 178 |
| 6 | 8％ | 171 |
| 7 | 2％ | 187 |
| 8 | 4％ | 168 |
| 9 | 6％ | 166 |
| 10 | 2％ | 194 |
| 11 | 4％ | 177 |
| 12 | 6％ | 170 |
| 13 | 4％ | 155 |
| 14 | 4％ | 167 |
| 15 | 8％ | 161 |
| 16 | 4％ | 179 |
| 17 | 4％ | 171 |
| 18 | 8％ | 162 |
By above experimental result is best during ratio 4% left and right sides of polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose sodium, hyprolose as can be seen, it is just not obvious that ratio reaches raising in 8% o'clock, the ratio of carboxymethylstach sodium is better at 8% o'clock, use separately cross-linked carboxymethyl cellulose sodium, hyprolose effect better, it is better that carboxymethylstach sodium and cross-linked carboxymethyl cellulose sodium mix result of use at 1: 1 in addition.
Selected prescription
By above experimental result, cooperate corresponding correctives again, optimize several groups of prescriptions, but scope of the present invention is not limited in this, its claimed scope is recorded in claim.
Prescription 1:
| Prescription | Per 1000 consumptions |
| Naloxone hydrochloride | 0.4g |
| Polyethylene glycol 6000 | 15g |
| Cross-linking sodium carboxymethyl cellulose | 0.8g |
| Mannitol | 3.6g |
| Aspartame | 0.2g |
Operating procedure:
Polyethylene glycol 6000 and naloxone hydrochloride, cross-linking sodium carboxymethyl cellulose, mannitol, aspartame are mixed 95 ± 5 ℃ of heating and meltings in back according to the above ratio and fully stir mixing.With Ф 1mm water dropper mixed liquor is splashed in the 0-40 ℃ of dimethicone, separate drop pill, draw coolant, drying, promptly.Every heavy 20mg of ball, hydrochloric naloxone 0.4mg.
Prescription 2:
| Prescription | Per 1000 consumptions |
| Naloxone hydrochloride | 0.4g |
| Polyethylene glycol 6000 | 12.5g |
| Poloxamer F68 | 2.5g |
| Carboxymethylstach sodium | 1.6g |
| Mannitol | 2.8g |
| Aspartame | 0.2g |
Operating procedure:
Polyethylene glycol 6000, poloxamer F68 and naloxone hydrochloride, carboxymethylstach sodium, mannitol, aspartame are mixed 85 ± 5 ℃ of heating and meltings in back according to the above ratio and fully stir mixing.With Ф 1mm water dropper mixed liquor is splashed in the 0-40 ℃ of dimethicone, separate drop pill, draw coolant, drying, promptly.Every heavy 20mg of ball, hydrochloric naloxone 0.4mg.
Prescription 3:
| Prescription | Per 1000 consumptions |
| Naloxone hydrochloride | 0.4g |
| Polyethylene glycol 6000 | 60g |
| Hyprolose | 3.2g |
| Mentholum | 0.4g |
| Sucrose | 16g |
Operating procedure:
Polyethylene glycol 6000 and naloxone hydrochloride, hyprolose, Mentholum, sucrose are mixed 95 ± 5 ℃ of heating and meltings in back according to the above ratio and fully stir mixing.With Ф 3mm water dropper mixed liquor is splashed in the 0-40 ℃ of dimethicone, separate drop pill, draw coolant, drying, promptly.Every heavy 80mg of ball, hydrochloric naloxone 0.4mg.
Prescription 4:
| Prescription | Per 1000 consumptions |
| Naloxone hydrochloride | 0.4g |
| Macrogol 4000 | 7.5g |
| Polyoxyethylene (40) stearate | 7.5g |
| Hyprolose | 0.8g |
| Sorbitol | 3.6g |
| Mentholum | 0.4g |
Operating procedure:
Macrogol 4000, polyoxyethylene (40) stearate and naloxone hydrochloride, hyprolose, sorbitol, Mentholum are mixed 100 ± 5 ℃ of heating and meltings in back according to the above ratio and fully stir mixing.With Ф 1mm water dropper mixed liquor is splashed in the 0-40 ℃ of dimethicone, separate drop pill, draw coolant, drying, promptly.Every heavy 20mg of ball, hydrochloric naloxone 0.4mg.
Prescription 5:
| Prescription | Per 1000 consumptions |
| Naloxone hydrochloride | 0.8g |
| Macrogol 4000 | 10g |
| Cetomacrogol 1000 0 | 5g |
| Carboxymethyl starch sodium | 0.4g |
| Polyvinylpolypyrrolidone | 0.4g |
| Sorbitol | 3.2g |
| Aspartame | 0.2g |
Operating procedure:
Macrogol 4000, cetomacrogol 1000 0 and naloxone hydrochloride, carboxymethyl starch sodium, polyvinylpolypyrrolidone are mixed 95 ± 5 ℃ of heating and meltings in back according to the above ratio and fully stir mixing.With Ф 1mm water dropper mixed liquor is splashed in the 0-40 ℃ of dimethicone, separate drop pill, draw coolant, drying, promptly.Every heavy 20mg of ball, hydrochloric naloxone 0.8mg.
Prescription 6:
| Prescription | Per 1000 consumptions |
| Naloxone hydrochloride | 1.6g |
| Polyethylene glycol 6000 | 10.8g |
| Carboxymethyl starch sodium | 0.4g |
| Cross-linking sodium carboxymethyl cellulose | 0.4g |
| Mannitol | 6.8g |
Operating procedure:
Macrogol 4000 and naloxone hydrochloride, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose are mixed 95 ± 5 ℃ of heating and meltings in back according to the above ratio and fully stir mixing.With Ф 1mm water dropper mixed liquor is splashed in the 0-40 ℃ of dimethicone, separate drop pill, draw coolant, drying, promptly.Every heavy 20mg of ball, hydrochloric naloxone 1.6mg.
Selected prescription analysis of experimental data
The prescription that screens is carried out indexs such as the preparation coefficient of variation, dissolve scattered time limit, presentation quality, hardness investigate (table 5).In addition, carry out influence factor's test, sample is positioned over high temperature (40 ℃), high humidity (60%), intense light irradiation (following 10 days mensuration of 4000 ± 500lxx) conditions content, contrast prescription and marketed tablet stability (table 6) respectively.By the contrast, drop pill aspect the coefficient of variation, mouthfeel, hydrothermal stability significantly better than marketed tablet.
Table 5: the heavy coefficient of variation of prescription ball, dissolve scattered time limit, outward appearance, mouthfeel are investigated
| Prescription | The coefficient of variation/% | Dissolve scattered time limit/sec | Presentation quality | Mouthfeel |
| Prescription 1 | 3.98 | 167 | Outstanding | Outstanding |
| Prescription 2 | 4.02 | 178 | Outstanding | Outstanding |
| Prescription 3 | 3.85 | 168 | Outstanding | Well |
| Prescription 4 | 8.89 | 282 | Well | Well |
| Prescription 5 | 4.66 | 169 | Well | Well |
| Prescription 6 | 4.78 | 159 | Well | Generally |
| Marketed tablet | 7.26 | 179 | Well | Generally |
Table 6: the 10 days factors influencing of writing out a prescription
| Prescription | High temperature (40 ℃) | High humidity (60%) | Intense light irradiation (4000 ± 500lxx) |
| Prescription 1 | 99.23％ | 98.26％ | 94.66％ |
| Prescription 2 | 99.24％ | 98.04％ | 94.83％ |
| Prescription 3 | 99.17％ | 98.51％ | 93.45％ |
| Prescription 4 | 99.15％ | 97.86％ | 93.90％ |
| Prescription 5 | 99.02％ | 98.16％ | 93.60％ |
| Prescription 6 | 99.16％ | 98.02％ | 93.79％ |
| Marketed tablet | 96.36％ | 96.47％ | 93.20％ |
Animal experiment
Adopt binary cycle intersection own control experimental design, with 6 male beasle dogs (body weight 10-12kg) is laboratory animal, measure prescription 1 Sublingual drop pill buccal administration (2mg/ bar) and marketed tablet drop pill buccal administration (2mg/ bar) blood drug level (seeing Table 7) at different time points (5min, 10min, 20min, 30min, 40min, 50min, 60min, 70min, 80min, 90min) venous blood, and calculate its corresponding pharmacokinetic parameter and relative bioavailability, result of calculation is listed in table 8.
Table 7: beasle dog Sublingual drop pill buccal administration (2mg/ bar) and marketed tablet buccal administration (2mg/ bar) different time points determination of plasma concentration (ng/ml)
Table 8: main pharmacokinetic parameter of beasle dog Sublingual drop pill buccal administration (2mg/ bar) and marketed tablet buccal administration (2mg/ bar) back and relative bioavailability.Test formulation: naloxone hydrochloride Sublingual drop pill; Reference preparation: naloxone hydrochloride sublingual lozenge.
Zooperal result shows: the bioavailability of naloxone hydrochloride Sublingual drop pill significantly is better than tablet (P＜0.05), and onset is faster, acts on stronger.
Claims (5)
1. naloxone hydrochloride Sublingual drop pill, it is mainly formed and is: naloxone hydrochloride 0.5%-8%, drop pill substrate 50%-90%, disintegrating agent 1%-8%, correctives 0.5%-40%.
2. naloxone hydrochloride according to claim 1 Sublingual drop pill, wherein drop pill substrate is one or more in polyethylene glycols, poloxamer, polyoxyethylene stearate (40) ester.
3. naloxone hydrochloride according to claim 1 Sublingual drop pill, wherein disintegrating agent is that in carboxymethylstach sodium, polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose sodium, the hyprolose one or more are used with.
4. naloxone hydrochloride according to claim 1 Sublingual drop pill, wherein correctives is one or more in mannitol, sorbitol, aspartame, Mentholum, the sucrose.
5. the described preparation of claim 1 is used for the treatment of application in acute alcoholism, narcosis analgesic acute poisoning, the narcosis analgesic drugs of addiction in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100921829A CN102000037A (en) | 2009-09-03 | 2009-09-03 | Sublingual naloxone hydrochloride dripping pill |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100921829A CN102000037A (en) | 2009-09-03 | 2009-09-03 | Sublingual naloxone hydrochloride dripping pill |
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| Publication Number | Publication Date |
|---|---|
| CN102000037A true CN102000037A (en) | 2011-04-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2009100921829A Pending CN102000037A (en) | 2009-09-03 | 2009-09-03 | Sublingual naloxone hydrochloride dripping pill |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016146981A1 (en) * | 2015-03-17 | 2016-09-22 | King's College London | Novel formulations |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1626083A (en) * | 2004-08-09 | 2005-06-15 | 复旦大学 | Powder and injection preparation of hydrochloric naloxone and preparation method |
| CN101036650A (en) * | 2006-03-16 | 2007-09-19 | 薛京 | Naloxone hydrochloride dropping pills |
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2009
- 2009-09-03 CN CN2009100921829A patent/CN102000037A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1626083A (en) * | 2004-08-09 | 2005-06-15 | 复旦大学 | Powder and injection preparation of hydrochloric naloxone and preparation method |
| CN101036650A (en) * | 2006-03-16 | 2007-09-19 | 薛京 | Naloxone hydrochloride dropping pills |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016146981A1 (en) * | 2015-03-17 | 2016-09-22 | King's College London | Novel formulations |
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Application publication date: 20110406 |