CN106361700A - Nalmefene hydrochloride nasal medicine administration preparation - Google Patents
Nalmefene hydrochloride nasal medicine administration preparation Download PDFInfo
- Publication number
- CN106361700A CN106361700A CN201611053453.6A CN201611053453A CN106361700A CN 106361700 A CN106361700 A CN 106361700A CN 201611053453 A CN201611053453 A CN 201611053453A CN 106361700 A CN106361700 A CN 106361700A
- Authority
- CN
- China
- Prior art keywords
- nalmefene
- administration preparation
- medicine
- nasal
- nalmefene hydrochloride
- Prior art date
- 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.)
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Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
Abstract
The invention provides a nalmefene nasal medicine administration preparation, which is prepared from nalmefene hydrochloride, nalmefene free alkali or pharmaceutically acceptable other nalmefene pharmaceutical salts and sorbefacients. A great number of experiments show that the nasal medicine administration preparation provided by the invention realizes the medicine absorption through a tunica mucosa nasi path, and the medicine enters blood circulation to achieve the effect; the advantages of stable performance, quality controllability and no stimulation on the tunica mucosa nasi can be realized. The nasal medicine administration preparation provided by the invention belongs to the intranasal medicine administration preparation capable of being used for shock resistance, overdose anesthesia rescue in an operation, morphine medicine poisoning and drug dependence person diagnosis, and prevention or treatment on stress diseases of acute alcoholism, cerebral infarction, neonatal asphyxia, drug poisoning and the like.
Description
Technical field
The present invention relates to nasal cavity administrated preparation, in particular to nose cavity administering formulation of nalmefene.
Background technology
Nalmefene hydrochloride (nalmefene hydrochloride) is opiate antagonist, public by U.S. ivax/ohmeda
Department's initiative, nineteen ninety-five lists in the U.S..It is to synthesize again after Allylnoroxymorphone (naloxone) and naltrexone (naltrexone)
One new pure opiate receptor antagonist.It all can be in conjunction with wherein strong with the effect of μ receptor binding with opiate receptor μ, κ, δ.
Nalmefene hydrochloride is pure opiate receptor antagonist, is the derivant of water solublity naltrexone, the chemistry of its 6 methylene
Structure, makes it show physiologically active higher, is more easy to penetrate biomembranous characteristic.Its plasma clearance half-life (t1/2) be
8.2-8.9h, with similar compound naltrexone (f=5%-20%, t1/2=2-5h) and naltrexone (f=0%-5%, t1/2=
1.5h) compare, its pharmacological action time length, action intensity are big.Toxic and side effects are relatively low.Though there is slight head in larger dose
Bitterly, asthenia, blurred vision etc., but no obvious adverse reaction, therefore, more and more interested to researchers.1984
Katovich et al. nalmefene carries out antagonism to relying on produced by morphine on rat model, and result shows, by per kilogram
0.001st, all there is remarkable result under 0.005,0.01,0.02 or 0.1mg nalmefene consumption.Nineteen ninety-five is ratified through U.S. fda, Na Mei
Sweet smell can be used for untoward reaction such as respiration inhibition, blood pressure reduction etc. that Post operation reverses opioid drug to cause.
At present clinically, the preparation of hydrochloric nalmefene is the oral formulations of oral administration and the note of vein and intramuscular delivery
Penetrate agent.To 1750 patient's administrated by injection, clinical trial shows not finding that it leads to disease or death (personal
Communication, s fein, anaquest, inc, may 1991)；Oral nalmefene 25,50,100mg when, do not produce
Coffee sample acts on (contracted pupil, sense of euphoria etc.), does not abuse potential.Experiment shows, nalmefene hydrochloride and nalmefene have effect
Time length, bioavailability are high, the feature of few side effects, have been used for respiration inhibition that antagonism opioid analgesicses cause and are used for
The treatment of heart failure, shock, alcoholism, addiction etc..
Practice also confirms that, though the nalmefene hydrochloride agent injection clinically using and oral formulations have certain therapeutic effect,
But onset is slow, it is administered onset in latter 30 minutes, tmaxMore than 1.5 hours.And through vein and administered intramuscular, must have specialty again
Medical personnel are operated.For the patient requiring the critical and stupor of convenient administration in time under the very first time, and it is in
For the patient of morbidity, provide a kind of route of administration in addition to injecting, being administered orally, a kind of alternative administration of many offers in other words
Approach undoubtedly seems very necessary.
Content of the invention
Although a kind of us 4,880,813 solution via intranasal application administration containing nalmefene disclosed in U.S. Patent, wherein drape over one's shoulders
Open country is to treat anaphylaxis Folium Nicotianae preparatum, for the local treatment of allergic rhinitises.Additionally, being silent on improving further treatment
The such as osmotic pressure regulator of effect, absorption enhancer, thickening agent one analog assistant.In other words, due to not using absorption enhancer,
Osmotic pressure regulator etc., local treatment is it is impossible to fully absorb internal and whole body plays a role.
The purpose of the present invention is to overcome the shortcomings of known nalmefene hydrochloride preparation, develops new nalmefene hydrochloride dosage form, non-
Injecting pathway and oral administration, and whole body plays a role, and has interests doctor, patient is convenient, and medication is quick.The present inventor is
By extensively and profoundly studying it has now been found that by nalmefene or its pharmaceutical salts and absorption enhancer, osmotic pressure regulator, thickening agent,
Preservative, or other pharmaceutic adjuvant is made into via intranasal application administration, it is low to be effectively prevented from nalmefene hydrochloride oral administration biaavailability, uses
Pharmaceutical quantities are big, turn avoid the not compliance of drug administration by injection simultaneously.
Many experiments show, the nasal cavity administrated preparation according to the present invention passes through nasal mucosa approach, by drug absorption, and enters
Blood circulation plays a role, and has the advantages that stable performance, quality controllable, non-stimulated to nasal mucosa.
The present invention has that absorption is rapid, and bioavailability is high, determined curative effect, feature easy to use, each dosage
Can adjust in the range of 0.1mg-40mg as needed.
The nalmefene preparation of the via intranasal application administration that the present invention provides includes nalmefene hydrochloride, nalmefene free alkali or pharmaceutically
Other pharmaceutical salts of acceptable nalmefene and absorption enhancer.
The second nalmefene preparation that the present invention provides includes osmotic pressure regulator.
The present invention provides the 3rd nasal-cavity administration nalmefene preparation to include preservative, surfactant and ph regulator.
The present invention provides the described absorption enhancer in the 4th nasal-cavity administration nalmefene preparation to be selected from following (1) (8)
In any one material:
(1) cyclodextrin that the cyclodextrin of α, β, gamma-cyclodextrin, and alkyl replaces, such as methyl-B-cyclodextrin, dimethyl-
Beta-schardinger dextrin-, HP-β-CD；
(2) cholic acid salt: as glycocholate, cholate, deoxycholate, cholyltaurine salt, glucose cholate, goose deoxygenate
Cholate, ursol deoxycholate；
(3) saturation and unsaturated fatty acid and its esters: such as lauric acid, Oleic acid, myristic acid, capric acid, laurate, monooctyl ester
Acid, certain herbaceous plants with big flowers acid esters, cetylate, ethyl lactate:
(4) alcohols: propylene glycol, isopropanol, hexadecanol, lauryl alcohol, oleyl alcohol etc.；
(5) ethers: polyoxyethylene laurel ether, polyoxyethylene octyl ether；
(6) sulfoxide type: such as dodecyl methyl sulfoxide, dimethyl sulfoxide；
(7) lactams: as dodecyl Azone, hold together cattle base Azone；
(8) ion-type nonionic face activating agent: as sodium lauryl sulphate, SUNSOFT 700P-2,
Tween 80, span 20 or their two or more mixture；
Described infiltration selected from Lactose, glucose, dextran, Sorbitol, Mannitol or its pharmaceutically acceptable inorganic salt
Pressure regulator；
Selected from macromolecular compound, carboxymethyl cellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyacrylic acid, acid polyethylene, card
Thickening agent described in POP；
Selected from ethyl hydroxybenzoate, p-Hydroxybenzoate, benzoic acid and its pharmaceutically acceptable salt, sorbic acid, the tertiary fourth of trichlorine
Preservative described in the cationic surfactant of alcohol, benzyl alcohol, phenethanol, thimerosal, chlorhexidine acetate and quaternary compound.
The present invention provides the 5th nasal-cavity administration nalmefene preparation, and by percent weight, described preparation contains 0.2-80%'s
Other salt of nalmefene hydrochloride, its free alkali or pharmaceutically acceptable nalmefene.
The present invention provides 80 milligrams of hydrochloric nalmefene in the 6th preparation described in 100 milliliters of nasal-cavity administration, polyethylene
0.5 gram of ketopyrrolidine, 0.5 milliliter of laurocapram, 1.0 grams of propylene glycol, 0.1 gram of ethyl hydroxybenzoate.
The present invention provides the preparation described in 100 milliliters of the 7th nasal-cavity administration nalmefene to include nalmefene hydrochloride 80 milli
Gram, 2.5 grams of hydroxypropyl b- cyclodextrin, 0.1 gram of ethyl hydroxybenzoate, 0.5 gram of Mannitol, 1.0 milliliters of PEG400, purified water
To 100 milliliters.
The present invention provides the preparation described in 100 milliliters of the 8th nasal-cavity administration nalmefene to include nalmefene hydrochloride 160 milli
Gram, 5 grams of methyl b- cyclodextrin, 0.1 gram of ethyl hydroxybenzoate, 0.5 gram of polyvinyl alcohol, Mannitol 2-4 gram, purified water is to 100 milliliters.
The administration nalmefene preparation of the nasal-cavity administration that the present invention provides is nasal mist or nasal cavity nasal drop.
The present invention provide nasal cavity administrated preparation can be used for shock, operation in overdose of anesthesia rescue, Morphinoid drug
Poisoning and the diagnosis of Drug Addicts, acute alcoholism, cerebral infarction, the stress disease such as asphyxia of newborn and drug intoxication
Prevention or the pernasal preparation for the treatment of.
According to the present invention, nalmefene hydrochloride or nalmefene other content in unit pernasal preparation for the pharmaceutical salts are
0.1-160% (weight %), preferably 0.2-80% (weight %).
Specific embodiment
Below by embodiment, the present invention will be further described, but it does not mean that and protection scope of the present invention is only limited
In this.
Embodiment 1: nalmefene hydrochloride spray
Ingredient amount
Nalmefene hydrochloride 80mg
Kollidon 0.5g
Laurocapram 0.5ml
Propylene glycol 1.0g
Ethyl hydroxybenzoate 0.1g
Distilled water is to 100ml
Preparation method: above-mentioned weight northylen ketopyrrolidine, nalmefene hydrochloride, propylene glycol, Laurel nitrogen statistics ethyl hydroxybenzoate are fully stirred
Even make all to dissolve, finally add distilled water to 100ml.Resulting solution is sub-packed in atomizing pump or quantitative pump.
Embodiment 2: nalmefene hydrochloride spray
Ingredient amount
Nalmefene hydrochloride 80mg
HP-β-CD 2.5g
Ethyl hydroxybenzoate 0.1g
Mannitol 0.5g
PEG400 1.0ml
Distilled water is to 100ml
Preparation method: by above-mentioned amount nalmefene hydrochloride, HP-β-CD, ethyl hydroxybenzoate, Mannitol add distilled water shaking make molten
Xie Hou, adds above-mentioned PEG400, finally adds distilled water to 100ml.
Embodiment 3: nalmefene hydrochloride spray
Ingredient amount
Nalmefene hydrochloride 160mg
Methyl-B-cyclodextrin 5g
Ethyl hydroxybenzoate 0.1g
Polyvinyl alcohol 0.5g
Mannitol 2-4g
Distilled water is to 100ml
Preparation method: above-mentioned amount nalmefene hydrochloride, methyl-B-cyclodextrin, ethyl hydroxybenzoate, polyvinyl alcohol are added distilled water, shaking makes
After all dissolving, finally add distilled water to 100ml.
Technical staff can carry out a variety of changes and change after reading present patent application description, but these changes and modification
All applying within pending claims.
Claims (2)
1. a kind of nalmefene hydrochloride preparation of the via intranasal application administration for the overdose of anesthesia rescue in shock, operation, its feature
It is, described in 100ml, preparation includes
80 milligrams of nalmefene hydrochloride,
2.5 grams of HP-β-CD,
0.1 gram of ethyl hydroxybenzoate,
0.5 gram of Mannitol,
1.0 milliliters of PEG400,
Purified water is to 100 milliliters.
2. a kind of nalmefene hydrochloride preparation of the via intranasal application administration for the overdose of anesthesia rescue in shock, operation, its feature
It is, described in 100ml, preparation includes
160 milligrams of nalmefene hydrochloride,
5 grams of methyl-B-cyclodextrin,
0.1 gram of ethyl hydroxybenzoate,
Mannitol 2-4 gram,
0.5 gram of polyvinyl alcohol,
Purified water is to 100 milliliters.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611053453.6A CN106361700A (en) | 2016-11-25 | 2016-11-25 | Nalmefene hydrochloride nasal medicine administration preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611053453.6A CN106361700A (en) | 2016-11-25 | 2016-11-25 | Nalmefene hydrochloride nasal medicine administration preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106361700A true CN106361700A (en) | 2017-02-01 |
Family
ID=57891569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611053453.6A Withdrawn CN106361700A (en) | 2016-11-25 | 2016-11-25 | Nalmefene hydrochloride nasal medicine administration preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106361700A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114096249A (en) * | 2019-07-09 | 2022-02-25 | 奥瑞克索股份公司 | Pharmaceutical composition for nasal delivery |
| EP3793558A4 (en) * | 2018-05-17 | 2022-04-20 | Aegis Therapeutics, LLC | Formulations and methods for the prevention of opioid overdose |
| US11458091B2 (en) | 2016-11-18 | 2022-10-04 | Opiant Pharmaceuticals, Inc. | Compositions and methods for the treatment of opioid overdose |
-
2016
- 2016-11-25 CN CN201611053453.6A patent/CN106361700A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11458091B2 (en) | 2016-11-18 | 2022-10-04 | Opiant Pharmaceuticals, Inc. | Compositions and methods for the treatment of opioid overdose |
| EP3793558A4 (en) * | 2018-05-17 | 2022-04-20 | Aegis Therapeutics, LLC | Formulations and methods for the prevention of opioid overdose |
| CN114096249A (en) * | 2019-07-09 | 2022-02-25 | 奥瑞克索股份公司 | Pharmaceutical composition for nasal delivery |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20170201 |
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| WW01 | Invention patent application withdrawn after publication |