CN1969814A - Nasal administered preparation of melatonin - Google Patents
Nasal administered preparation of melatonin Download PDFInfo
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- CN1969814A CN1969814A CNA2005101238906A CN200510123890A CN1969814A CN 1969814 A CN1969814 A CN 1969814A CN A2005101238906 A CNA2005101238906 A CN A2005101238906A CN 200510123890 A CN200510123890 A CN 200510123890A CN 1969814 A CN1969814 A CN 1969814A
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Abstract
The invention relates to a nasal administration preparation comprising melatonin and at least one kind of polyethylene glycol selected from polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, or polyethylene glycol 600.
Description
Technical field
The present invention relates to a kind of nasal cavity administrated preparation that contains melatonin, it comprises melatonin and is selected from the Polyethylene Glycol of at least a Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600.
Background technology
Melatonin is a kind of indoles hormone that the human pineal gland secretion produces, and has effects such as hypnotic, slow down aging, enhance immunity and antitumor.Melatonin has its unique advantage as a kind of novel hypnotic: (1) is low dose of (just to have comparatively ideal hypnotic effect under 0.1～0.3mg); (2) melatonin is a kind of endogenic material, work by adjusting to hormonal system, and concerning body foreign body, the metabolic pathway of himself is arranged in vivo, can not cause female medicine and metabolite thereof to accumulate in vivo; (3) the melatonin biological half-life is short, promptly reduces to normal person's physiological level after oral several hours, can not influence the energy of next day because of concentration remnants, even and drug dependence or excessive use take place, life danger can not take place generally yet; (4) toxicity is minimum, can not survey its LD in the zoopery
50, heavy dose of (800mgkg
-1) time do not cause rats death yet, big again dosage is because of being subjected in the water restriction of dissolubility impossible.
Melatonin is very unstable in the oral absorption of human body, and first pass effect is obvious, and the melatonin of same dosage can have 10～20 times difference in Different Individual, and in addition, the oral administration onset is slower.For this reason, people have inquired into the feasibility of the non-oral administration of melatonin.1980, HoechstAG applied for a Japan Patent J55057563, and prescription consists of the 100mg melatonin and is dissolved in the alcoholic solution of 10ml5% in this patent, but there is serious side reaction in this prescription.Another prescription is formed employing propylene glycol solubilising in this patent, but propylene glycol has serious side reaction to nasal mucosa equally.PCT patent application WO98/42333 and U.S. Pat 6007834 have also disclosed a kind of nasal cavity administrated preparation that contains melatonin, wherein adopt cyclodextrin compounds or glycerol solubilising.
Summary of the invention
The purpose of this invention is to provide a kind of new nasal cavity administrated preparation that contains melatonin, and preparation method thereof.The inventor finds after deliberation, and it is rapid, rapid-action that the nasal cavity preparation that Polyethylene Glycol and melatonin form demonstrates drug absorption, and high characteristics of absolute bioavailability and be better than the nasal administered preparation of melatonin of known report.
Therefore, the present invention relates to a kind of nasal cavity administrated preparation, it comprises melatonin and is selected from least a Macrogol 200, Liquid Macrogol, the Polyethylene Glycol of PEG400 or Macrogol 600.
According to the present invention, nasal cavity administrated preparation of the present invention also comprises at least a pH buffer agent, antiseptic, stabilizing agent, penetrating agent, aromatic and osmotic pressure regulator.
People's nasal membrane surface area reaches 150 square centimeters, and the top layer epithelium has a large amount of nose ciliums, and it not only can remove foreign body, prevents that airborne granule from entering pulmonary; And can prevent ectogenic albumen, virus and antibacterial are inhaled in the body, are the important immunologic barriers of body.Therefore, extremely important for keeping the human body normal physiological function.Nasal cavity administrated preparation must be less for nose cilium zest.Nasal administered preparation of melatonin of the present invention has the advantage little to nasal ciliary toxicity.
Term among the present invention " melatonin " is original shape medicine melatonin or its pharmaceutically acceptable salt or its halo derivatives, described acceptable salt comprises hydrochlorate, sulfate, nitrate, acetate, citrate, tartrate, mesylate and maleate, or its esters derivative, as: benzoate etc.
Per 1 milliliter or per 1 restrain in the agent and contain the melatonin that is equivalent to 0.1-100mg of nasal cavity administrated preparation of the present invention is preferably 1-50mg.
Nasal administered preparation of melatonin of the present invention can be spray, powder agent, nasal drop, ointment, gel, membrane, Emulsion or microparticle formulation.
The Polyethylene Glycol that is adopted in the nasal administered preparation of melatonin of the present invention is one or more in the Polyethylene Glycol compounds, wherein Polyethylene Glycol is liquid Polyethylene Glycol, as Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600 etc.
The pH buffer agent that adopts among the present invention can be acetate buffer salt, citric acid buffer salt, carbonic acid buffer salt and phosphate-buffered salt, and concentration is 0.1mol/L-0.2mol/L.
The present invention adopts the macromolecular compound cellulose derivative that preparation toughness is regulated, can select methylcellulose, sodium carboxymethyl cellulose, HPMC, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvidone, carbomer, polyvinyl alcohol, alginate, xanthan gum, arabic gum, tragacanth, chitosan etc. for use, with the time of contact of prolong drug and nasal mucosa, improve bioavailability.
Antiseptic of the present invention is selected p-Hydroxybenzoate, benzoic acid and salt thereof, sorbic acid, chlorobutanol, benzyl alcohol, phenethanol, chlorhexidine acetate, thimerosal and quaternary ammonium compound cationoid surfactant etc. for use, and described antiseptic is harmless in pressing down the mattress concentration range, nonirritant, no off-odor, do not influence the physicochemical property of preparation.
The stabilizing agent that is added in the preparation of the present invention has antioxidant such as sodium pyrosulfite, sodium sulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, thiourea, cysteine, tocopherol and lecithin etc.The preferred of aforementioned stable agent consumption is the 0.01%-5% (w/v) of preparation.Other has chelating agen, as ethylenediaminetetraacetic acid, disodiumedetate, citric acid, tartaric acid etc.The preferred of disodiumedetate consumption is 0.005%-0.05% (w/v).
Penetrating agent of the present invention is cyclic peptide classes such as surfactants such as sodium laurylsulfate, chlolic acid derivatives, taurine, hyaluronic acid, tween, span, Brij30 and bacitracin.Its consumption is about 0.005%-10%, and preferred amounts is 0.01%-5%.Above-mentioned substance has solubilising, emulsification simultaneously.
Penetrating agent also can be 1-ephedrine, d-ephedrine, 1-pseudoephedrine, d-pseudoephedrine, menthol, Borneolum Syntheticum.
Aromatic of the present invention can be one or more in cinnamic aldehyde, vanillin, the Oleum menthae.
Osmotic pressure regulator of the present invention can be one or more in sodium chloride, glucose, lactose, mannose, the mannitol.Wherein, the concentration of sodium chloride is in the 0.6%-1.2% scope.
The present invention also can adopt natural macromolecular materials such as biodegradable synthesized polymer materials such as polylactic acid, glycolide-lactide copolymer and albumin, gelatin, starch to be used to prepare microparticle formulation.
Preparation of the present invention can be by this area conventional method preparation, for example with melatonin and Polyethylene Glycol, and necessary or optionally and other pharmaceutic adjuvant mix.
The specific embodiment
Embodiment 1 melatonin nasal spray (the 15mg melatonin/ml)
Melatonin 1.5g
PEG400 15ml
EDTA-2Na 0.01g
Sodium sulfite 0.15g
Ethylparaben 0.1g
Sodium chloride 0.9g
Water for injection adds to 100ml
Be prepared into clarifying yellow solution by above-mentioned prescription, be sub-packed in the quantitative atomizing pump, promptly get nasal spray T1.
With reference to PCT patent WO98/42333, design is following writes out a prescription in addition:
Melatonin 1.5g
Hydroxypropyl beta cyclodextrin 13g
EDTA-2Na 0.01g
Vitamin C 0.2g
Benzalkonium chloride 0.1g
Sodium chloride 0.9g
Water for injection adds to 100ml
Be prepared into clarifying yellow solution by above-mentioned prescription, be sub-packed in the quantitative atomizing pump, promptly get nasal spray T2.
Other prepares the melatonin intravenous injection R of 3mg/ml.Get 6 of healthy new zealand rabbits, male, body weight 2.5～3.5kg.Animal subject is divided into 3 groups at random, gives nasal spray T1 (15mg/ml*100ul), T2 (15mg/ml*100ul) and intravenous injection R (3mg/ml*0.5ml) by 3*3 Latin square design intersection, the cleaning phase is 7d.Respectively at before the administration and after the administration 2,5,10,20,30,45,60,90min gets blood 1.2ml from auricular vein and puts in the centrifuge tube that contains heparin, centrifugal immediately, separated plasma, frozen HPLC analysis, the absolute bioavailability of calculating spray T1, T2 of carrying out to taking a sample in-20 ℃ of refrigerators.Table 1 is a blood drug level after the different approaches administration, and table 2 is the comparison of area under the drug-time curve AUC in the rabbit plasma after the different approaches administration.
Blood drug level under table 1 different way of administration (n=6)
The result reaches peak value at 5 minutes blood drug level after showing nasal-cavity administration, and blood drug level is very high in the time of 2 minutes, soon near peak value.
Area under the drug-time curve (AUC under table 2 different way of administration
0-60) and bioavailability (n=6)
By last table result as seen, absolute bioavailability by the melatonin nasal spray T1 of the present invention preparation is 85.2 ± 26.3%, absolute bioavailability by the nasal spray T2 of PCT patent WO98/42333 preparation is 44.2 ± 14.2%, ANOVA showed significant, absolute bioavailability has significant difference (P＜0.05) between two preparations.
Nasal spray T1 is adopted the Bufo siccus maxillary model evaluation cilium toxicity that exsomatizes.The Bufo siccus maxillary mucomembranous cilium persistent movement time that it has been generally acknowledged that test group is more than 60% of physiology saline control group, and then the cilium toxicity of test preparation is less.The cilium toxicity that confirms this nasal cavity administrated preparation through test is more than 60% of physiology saline control group.
Embodiment 2 melatonin nasal powders
Melatonin 1.5g
Lactose 30g
Sodium sulfite 0.15g
Distilled water adds to 100ml
Above-mentioned melatonin and lactose are added in the 100ml distilled water, be stirred to dissolving fully ,-35 ℃ of lyophilized overnight respectively at lyophilization 24h under-10 ℃ and the 0 ℃ of condition, are crossed 100 mesh sieves again, suck usefulness for nasal cavity.
Embodiment 3 melatonin microball preparations
Melatonin 1.5g
Span?80 1.0g
Gelatin 6.0g
Medicinal castor oil 100ml
The toluene solution of saturated glutaraldehyde is an amount of
Get above-mentioned gelatin and be dissolved in the 30ml55 ℃ of water, add the melatonin dissolving.Other gets it filled and adds emulsifying agent Span80 in dry beaker with Oleum Ricini, and beaker is placed 50 ℃ of water-baths, under agitation slowly adds in the gelatin solution of pastille, and mixing speed is 1000 rev/mins.The toluene solution that adds saturated glutaraldehyde behind the stirring 10min continues to stir 2h, uses normal hexane: isopropyl alcohol (1: 1) washing.Wash with ether through centrifugal thus obtained microsphere, drying, screening back packing is used.
Embodiment 4 melatonin gels
Melatonin 1.5g
Carbopol 934 1.5g
Glycerol 10g
Sodium sulfite 0.15g
Distilled water adds to 100ml
Carbopol 934 is mixed swelling with the 30ml distilled water, add melatonin, glycerol, sodium sulfite again and fully stir evenly, promptly get clear gel.
The present invention describes by above description and embodiment, more than is described as nonrestrictively, does not limit claim scope of the present invention.
Claims (8)
1, a kind of nasal cavity administrated preparation, it comprises the original shape medicine of melatonin or its pharmaceutically acceptable salt or its esters derivative or its halo derivatives and at least a Polyethylene Glycol that is selected from Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600.
2, nasal cavity administrated preparation according to claim 1, wherein per 1 milliliter or per 1 gram contain the melatonin original shape medicine that is equivalent to 0.1-100mg in the described nasal cavity administrated preparation.
3, nasal cavity administrated preparation according to claim 1 and 2, wherein per 1 milliliter or per 1 gram contain the melatonin original shape medicine that is equivalent to 1-50mg in the described nasal cavity administrated preparation.
4, according to the arbitrary described nasal cavity administrated preparation of claim 1-3, wherein said nasal cavity administrated preparation is spray, powder agent, nasal drop, ointment, gel, membrane, Emulsion or microparticle formulation.
5, the preparation arbitrary according to claim 1-4, wherein as required, described preparation also contains at least a pH buffer agent, thickening agent, antiseptic, stabilizing agent, penetrating agent, aromatic and osmotic pressure regulator.
6, preparation according to claim 5, wherein said pH buffer agent is an acetate, one or more in citrate, carbonate and the phosphate, concentration is 0.1mol/L-0.2mol/L; Described thickening agent is one or more in methylcellulose, sodium carboxymethyl cellulose, HPMC, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvidone, carbomer, polyvinyl alcohol, alginate, xanthan gum, arabic gum, tragacanth, the chitosan; Described antiseptic is one or more in p-Hydroxybenzoate, benzoic acid and salt thereof, sorbic acid, chlorobutanol, benzyl alcohol, phenethanol, chlorhexidine acetate, thimerosal and the quaternary ammonium compound cationoid surfactant; Described stabilizing agent is one or more in sodium pyrosulfite, sodium sulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, thiourea, cysteine, tocopherol, edta and its sodium salt, tartaric acid and the lecithin, and concentration is 0.005%-5% (w/v); Described penetrating agent is one or more of cyclic peptide apoplexy due to endogenous wind such as surfactants such as sodium laurylsulfate, chlolic acid derivatives, taurine, hyaluronic acid, tween, span, polyoxyethylene-lauryl alcohol and bacitracin, or 1-ephedrine, d-ephedrine, 1-pseudoephedrine, d-pseudoephedrine, menthol, Borneolum Syntheticum, concentration are 0.005%-10%; Described aromatic is one or more in cinnamic aldehyde, vanillin, the Oleum menthae; Described osmotic pressure regulator is one or more in sodium chloride, glucose, lactose, mannose, the mannitol, and concentration is 0.6%-1.2%.
7, preparation according to claim 4, wherein said microparticle formulation are gelatin, starch, albumin, polylactic acid, glycolide-lactide copolymer.
8, the preparation of claim 5 contains the 15mg melatonin in wherein every ml or the described preparation of every gram.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510123890A CN1969814B (en) | 2005-11-24 | 2005-11-24 | Nasal administered preparation of melatonin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510123890A CN1969814B (en) | 2005-11-24 | 2005-11-24 | Nasal administered preparation of melatonin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1969814A true CN1969814A (en) | 2007-05-30 |
| CN1969814B CN1969814B (en) | 2010-05-26 |
Family
ID=38110963
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200510123890A Expired - Fee Related CN1969814B (en) | 2005-11-24 | 2005-11-24 | Nasal administered preparation of melatonin |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20112042A1 (en) * | 2011-11-10 | 2013-05-11 | Eratech S R L | POWDER TO RECONSTITUTE BEFORE INCLUDING MELATONIN AND INJECTABLE PREPARATION OBTAINABLE FROM SUCH POWDER. |
| CN104739827A (en) * | 2015-02-13 | 2015-07-01 | 厦门艾赛生物科技有限公司 | External-use preparation for improving sleep |
| CN105663061A (en) * | 2014-11-16 | 2016-06-15 | 刘佳迪 | Preparation method and application method for melatonin dropping pill |
| CN105687186A (en) * | 2015-12-31 | 2016-06-22 | 卢秋妤 | Sleeping medicinal preparation for external use and preparation method thereof |
| CN107028941A (en) * | 2017-05-23 | 2017-08-11 | 丝里伯创新孵化深圳有限公司 | A kind of sleep aid and preparation method thereof and application method, atomizer |
| CN107184409A (en) * | 2017-05-26 | 2017-09-22 | 西宝生物科技（上海）股份有限公司 | Melatonin slow-release nasal cavity health-care perfume with sleep-promoting effect and preparation method thereof |
| WO2019161470A1 (en) * | 2018-02-22 | 2019-08-29 | Cosmed Indústria De Cosméticos E Medicamentos S.A. | Pharmaceutical composition in the form of an aqueous suspension and use of a pharmaceutical composition in the form of an aqueous suspension |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1112184C (en) * | 1998-04-13 | 2003-06-25 | 广州市美乐健生物技术有限公司 | Melatonin slow-releasing agent and its production process |
-
2005
- 2005-11-24 CN CN200510123890A patent/CN1969814B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20112042A1 (en) * | 2011-11-10 | 2013-05-11 | Eratech S R L | POWDER TO RECONSTITUTE BEFORE INCLUDING MELATONIN AND INJECTABLE PREPARATION OBTAINABLE FROM SUCH POWDER. |
| WO2013068565A3 (en) * | 2011-11-10 | 2014-05-01 | Eratech S.R.L. | Melatonin-based solutions and powders for their preparation |
| CN105663061A (en) * | 2014-11-16 | 2016-06-15 | 刘佳迪 | Preparation method and application method for melatonin dropping pill |
| CN104739827A (en) * | 2015-02-13 | 2015-07-01 | 厦门艾赛生物科技有限公司 | External-use preparation for improving sleep |
| CN105687186A (en) * | 2015-12-31 | 2016-06-22 | 卢秋妤 | Sleeping medicinal preparation for external use and preparation method thereof |
| CN107028941A (en) * | 2017-05-23 | 2017-08-11 | 丝里伯创新孵化深圳有限公司 | A kind of sleep aid and preparation method thereof and application method, atomizer |
| CN107184409A (en) * | 2017-05-26 | 2017-09-22 | 西宝生物科技（上海）股份有限公司 | Melatonin slow-release nasal cavity health-care perfume with sleep-promoting effect and preparation method thereof |
| WO2019161470A1 (en) * | 2018-02-22 | 2019-08-29 | Cosmed Indústria De Cosméticos E Medicamentos S.A. | Pharmaceutical composition in the form of an aqueous suspension and use of a pharmaceutical composition in the form of an aqueous suspension |
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| Publication number | Publication date |
|---|---|
| CN1969814B (en) | 2010-05-26 |
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