CN106963736A - Dextromethorphan hydrobromide sustained-release dry suspensoid agent and preparation method thereof - Google Patents
Dextromethorphan hydrobromide sustained-release dry suspensoid agent and preparation method thereof Download PDFInfo
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- CN106963736A CN106963736A CN201610030903.3A CN201610030903A CN106963736A CN 106963736 A CN106963736 A CN 106963736A CN 201610030903 A CN201610030903 A CN 201610030903A CN 106963736 A CN106963736 A CN 106963736A
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- dextromethorphan hydrobromide
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- sustained
- release
- agent
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- 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
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- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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Abstract
The invention discloses the slow-release dry suspension for the dextromethorphan hydrobromide being sustained in gastrointestinal tract environment.Said preparation contains dextromethorphan hydrobromide and pharmaceutically acceptable polymer.Said preparation 10-90% containing dextromethorphan hydrobromide by weight percentage, auxiliary material is 10-90%.The auxiliary material for playing slow releasing function is cationic ion-exchange resin and methylcellulose, ethyl cellulose, acrylic resin, HPMC one or more therein.Compared with quick releasing formulation, controlled release preparation of the present invention can keep effective blood drug concentration in 24 hours, improve curative effect, and toxic side effect is small, take, easy to carry, and number of times is taken in reduction.Sustained release preparation of the present invention can keep more stably blood concentration in 24 hours, improve curative effect, and toxic side effect is small.This preparation only needs be administered once for one day.Controlled release preparation of the present invention will be used clinically as antitussive.
Description
Technical field
The present invention relates to antitussive dextromethorphan hydrobromide sustained-release dry suspensoid agent with and preparation method thereof.
Background technology
Dextromethorphan (dextromethorphan) is the dextroisomer of m orphine levo-dromoran methyl ether, by suppressing
The reflection of oblongata coughing centre plays central antitussive effect to improve central nervous system cough threshold value.Its antibechic intensity with can
Treat because equal or slightly strong.But analgesia and sedation without codeine, prolonged application have no tolerance and additive.Therapeutic dose
Respiratory center and respiratory mucosa secretion are not suppressed, significantly, adverse reaction rate is low, oral absorption for clinical practice antibechic effect
It is good, work within 15~30 minutes, effect can be maintained 3~6 hours, t1/2 is 5 hours.Because of its non-narcotic central antitussive effect
It is widely used in clinical antibechic treatment.
General preparation, often needs to be administered several times for 1st, such as conventional tablet is administered 3 times on the 1st, and 1 to 2 tablets once (15mg/ pieces).Cause
Pain, the reason patient such as dislike trouble can consciously or unconsciously change Dosing Regimens, miss once or twice, the medicine in blood plasma and tissue
Level concentration rises and falls big, even if continuing medication, treatment concentration is not reached in a short time yet, can only repeated drug taking could rebuild treatment water
It is flat, not only waste medicine but also delay treatment.
Oral sustained-release preparation, which is meant, can extend medicine effect in vivo, reduce a class newtype drug system of medicining times
Agent, with toxic side effect is reduced, the advantages of improving the tolerance of patient and the blood concentration of lasting stability be provided.But suitable child
And the formulation and preparation of the particular patients ' such as old man are very limited.Due to this kind of patient and difference of the adult in physiological function,
In addition to the difference of dosage, the compliance of requirement and medication to formulation also has a different requirements, sustained release tablet for oral use or
The solid pharmaceutical preparation Chang Yinwei such as capsule mouthfeels are uncomfortable or dysphagia and the problems such as be difficult divided dose, and cause such patient's
Take inconvenience, influence the completion of normal therapeutic scheme and the performance of drug effect, some film control formula pieces or sustained release tablets split it is broken after take,
Even occur serious side effects.And by contrast, slow-release dry suspension have absorb it is fast, can divided dose take, readily packaged fortune
It is defeated, the characteristics of easily received by old man and children.Therefore research and develop slow-release dry suspension in good taste and that drug effect can be extended by
To the great attention of medicament scholar and clinician.
Although slow-release dry suspension has more advantage relative to common sustained release preparation and has obtained medicament scholar and clinician
Great attention, but prior art only has the sustained release preparation of dextromethorphan hydrobromide, can only achieve external slow release effect in vivo, also
In the absence of the controlled release dry suspensoid agent of ambroxol hydrochloride.Applicant believes that this at least partly because dextromethorphan hydrobromide it is some
Physical property is unfavorable for being prepared as conventional slow-release dry suspension, therefore prepares the sustained release of dextromethorphan hydrobromide
Dry mixed suspension preparation technically has bigger difficulty to those skilled in the art.
The present inventor is by creatively using two kinds of technologies of ion exchange and WURST fluidized bed coatings film simultaneously
Carry out Drug controlled release, the dextromethorphan hydrobromide sustained-release dry suspensoid agent of realizing controlled-release has unexpectedly been obtained, so that hydrogen
Blood concentration is more steady in bromic acid dextromethorphan body, and drug effect is more longlasting.
The content of the invention
It is contemplated that by creatively simultaneously using two kinds of technologies of ion exchange and coating membrane come Drug controlled release,
The dextromethorphan hydrobromide new sustained release dry suspensoid agent being administered once for a kind of one day is prepared, patient need to only take once daily
It can reach therapeutic effect.The present invention is directed to the deficiency of existing preparation, and hydrogen bromine is determined according to the consumption per day of sustained release preparation one has been listed
Sour dextromethorphan consumption is 60mg, to ensure the validity of novel formulation.Property further according to dextromethorphan hydrobromide is carried out largely
Preparation research, complete the development work of the slow-release dry suspension that is administered once on the one.The invention mainly comprises main ingredient, retardance
Agent, impregnating agent, plasticizer, other auxiliary materials compositions such as supensoid agent.
Slow-release material selected by the present invention may be selected from cationic ion-exchange resin and methylcellulose, ethyl cellulose, third
Olefin(e) acid resin, HPMC one or more therein.
Impregnating agent may be selected from the one or more in methylcellulose, glycerine, PEG4000 etc..
Plasticizer may be selected from the one or more in diethyl phthalate, dibutyl sebacate, PEG400 etc..
Supensoid agent may be selected from the one or more in PVP, HPMC, tragcanth, Carbopol, Avicel RC591 etc..
Flavouring may be selected from mannitol, xylitol, Stevioside, lactose, fructose, sucrose, protein sugar, maltitol, radix glycyrrhizae
Glucin, Sodium Cyclamate, gelatin, Aspartame, flavoring banana essence, flavoring pineapple essence, vanillic aldehyde, fragrant citrus essence, flavoring orange essence,
Mint Essence, ginseng essence, strawberry essence, citric acid, citric acid etc..
In order to ensure the stabilization of main ingredient, appropriate antioxidant and preservative etc. can also be added.
Brief description of the drawings
Fig. 1 is the In-vitro release curves figure of the dry mixed suspension preparation of dextromethorphan hydrobromide sustained-release prepared according to embodiment 1.
Fig. 2 is that the dry mixed suspension preparation of dextromethorphan hydrobromide sustained-release prepared according to embodiment 1 often releases piece with commercially available
Releasing curve diagram in beagle dog bodies.
Embodiment
Preparation technology：
1. the preparation of medical resin
Cationic ion-exchange resin is added to appropriate deionized water, medicine is added under agitation and is mixed, timing sampling is determined
The concentration of drug in solution.It is balance to be achieved when drug concentration no longer time to time change, resin is washed with deionized water
The uncombined medicine on surface, load medicated resin is drying to obtain at 40 DEG C -60 DEG C.
2. the dipping of medical resin
Take load medicated resin appropriate, in the aqueous solution for the PEG4000 for adding 20%, stir 0.5 hour, drying and screening must impregnate
Medical resin.
3. the preparation of medical resin micro-capsule
Using bottom spraying type fluid unit, the medical resin 150g of 180~200 μm of dipping is put into fluidising chamber, made
With nozzle diameter 1mm spray gun, regulation air quantity makes particle in fluidising chamber in preferable fluidized state, and atomization gas pressure is adjusted to
0.15Mpa, coating solution is at the uniform velocity pumped into constant flow pump, makes coating solution atomizing effect good, continuous coating Non-intermittent drying time, really
Substantially without adhesion phenomenon between particulate in guarantor's coating process.
4. the preparation of medical resin micro-capsule dry suspensoid agent
Take drug-resin micro-capsule and load medicated resin a certain amount of, suspending agent (PVP, HPMC, tragcanth, Carbopol,
One or more in Avicel RC591 etc.) in right amount, it is well mixed to produce drug-resin controlled release dry suspensoid agent.In addition, in order to
Improve the taste of dry suspensoid agent, appropriate flavouring, such as mannitol, xylitol, Stevioside, lactose, fructose, sugarcane can also be added
Sugar, protein sugar, maltitol, glycyrrhizin, Sodium Cyclamate, gelatin, Aspartame, flavoring banana essence, flavoring pineapple essence, perfume (or spice)
Lan Su, fragrant citrus essence, flavoring orange essence, Mint Essence, ginseng essence, strawberry essence, citric acid, citric acid etc..In order to ensure master
The stabilization of medicine, can also add appropriate antioxidant and preservative etc..
Following examples are intended to the present invention be further illustrated and its unrestricted scope.
Embodiment
According to foregoing preparation technology, the ambroxol hydrochloride controlled release suspension of the present invention is prepared using following prescriptions.
Embodiment 1：
Embodiment 2：
Embodiment 3：
The vitro release experiment of the dextromethorphan hydrobromide sustained-release dry suspensoid agent of experimental example 1
In vitro test is that screening prescription determines the important means of technique, and has important work to the quality control of preparation
With mainly being investigated by dissolution rate.The present invention uses the 500ml 0.4mol/l KCl of degassed processing for dissolution medium：
Rotating speed 100r/min, 37 DEG C of temperature.According to 2000 editions annex XC paddle method operations of Chinese Pharmacopoeia, taken respectively at 2,4,6,8,12,24h
Sample 5ml, filters through 0.45 μm of miillpore filter, discards primary filtrate, take subsequent filtrate standby, synthermal, the phase of same volume is added in time
Medium is answered, subsequent filtrate is determined into absorbance at 278nm, different time sample liquid concentration is calculated according to standard curve, 12 are investigated
The Cumulative release amount and the relation of time of hour.
Experimental result is as shown in fig. 1.As a result show, prepared dextromethorphan hydrobromide sustained-release is dry-mixed in embodiment 1
The vitro release of suspension 12 hours is 75%-85%, it is thus possible to medicine is slowly discharged into vivo.
The stability experiment of the dextromethorphan hydrobromide sustained-release dry suspensoid agent of experimental example 2
The dextromethorphan hydrobromide sustained-release dry suspensoid agent being made according to the present invention high temperature, high humidity, illumination, exposure have been subjected to
Air is tested, and as a result shows this product under conditions of high temperature, high humidity, illumination, exposure air, stability is preferable.
The interior medicine dynamics research of the dextromethorphan hydrobromide sustained-release dry suspensoid agent of experimental example 3
Pharmacokinetics (pharmacokinetics) is the principle and mathematical processing methods of applied dynamics, is quantitatively retouched
The dynamic rule of the processes such as absorption, distribution, metabolism and excretion that medicine enters in body by all means is stated, that is, is studied
Present site, concentration and the relation between the time of internal medicine, and the relationship required for these data that provide an explanation
Science.
Using high performance liquid chromatography as detection method, dextromethorphan hydrobromide sustained-release dry suspensoid agent has been carried out
Beagle dogs Internal pharmacokinetics are studied.As a result it is as shown in Figure 2.As a result dextromethorphan hydrobromide sustained-release dry suspensoid agent is shown in vivo
Drug release is more steady than sustained release tablets, and duration of efficacy is longer.
As described above, the present invention's can realize improved controlled release effect comprising dextromethorphan hydrobromide sustained-release dry suspensoid agent
Fruit is there is provided improved dissolution rate and stability, and effective blood concentration can be provided daily by being only administered once.
Although describing the present invention according to above-mentioned specific embodiment, it will be recognized that, those skilled in the art
Various modifications and transformation may be made to the present invention, and these modifications and transformation are also belonged to defined in appended claims
In the scope of the present invention.
Claims (5)
1. the dry mixed suspension preparation of dextromethorphan hydrobromide sustained-release, by weight percentage said preparation contain following composition：
Dextromethorphan hydrobromide 10-90%
Play the auxiliary material 10-90% of slow releasing function
Other auxiliary material surpluses.
2. the dry mixed suspension preparation of dextromethorphan hydrobromide sustained-release according to claim 1, it is characterised in that play slow releasing function
Auxiliary material is cationic ion-exchange resin and methylcellulose, ethyl cellulose, acrylic resin, HPMC therein one
Plant or several.
3. the dry mixed suspension preparation of dextromethorphan hydrobromide sustained-release according to claim 1, it is characterised in that other auxiliary materials
One or more in retarding agent, impregnating agent, plasticizer and suspending agent.
4. the dry mixed suspension preparation of dextromethorphan hydrobromide sustained-release according to claim 1 or 2 or 3, it is characterised in that the system
Agent is the dry mixed suspension preparation of solid.
5. prepare the method for the dry mixed suspension preparation of dextromethorphan hydrobromide sustained-release according to one of claim 1-4, the side
Method comprises the following steps：
1) the load medicated resin for being loaded with dextromethorphan hydrobromide is prepared；
2) the load medicated resin is impregnated；
3) prepare and carry loblolly tree lipid microvesicle；
4) dry suspensoid agent is prepared using above-mentioned load loblolly tree lipid microvesicle.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610030903.3A CN106963736A (en) | 2016-01-14 | 2016-01-14 | Dextromethorphan hydrobromide sustained-release dry suspensoid agent and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610030903.3A CN106963736A (en) | 2016-01-14 | 2016-01-14 | Dextromethorphan hydrobromide sustained-release dry suspensoid agent and preparation method thereof |
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| Publication Number | Publication Date |
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| CN106963736A true CN106963736A (en) | 2017-07-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610030903.3A Pending CN106963736A (en) | 2016-01-14 | 2016-01-14 | Dextromethorphan hydrobromide sustained-release dry suspensoid agent and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109106687A (en) * | 2018-09-14 | 2019-01-01 | 广州大光制药有限公司 | A kind of Pidotimod dry suspension and preparation method thereof |
| CN109771372A (en) * | 2019-03-26 | 2019-05-21 | 江苏四环生物制药有限公司 | A kind of dextromethorphan hydrobromide sustained-release suspension and preparation method thereof |
| CN111603456A (en) * | 2020-07-08 | 2020-09-01 | 江苏四环生物制药有限公司 | Carbixamine maleate controlled-release dry suspension and preparation method thereof |
| CN117017911A (en) * | 2023-08-15 | 2023-11-10 | 山东则正医药技术有限公司 | Dextromethorphan hydrobromide sustained-release suspension and preparation method thereof |
| CN117017911B (en) * | 2023-08-15 | 2024-06-07 | 山东则正医药技术有限公司 | Dextromethorphan hydrobromide sustained-release suspension and preparation method thereof |
-
2016
- 2016-01-14 CN CN201610030903.3A patent/CN106963736A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109106687A (en) * | 2018-09-14 | 2019-01-01 | 广州大光制药有限公司 | A kind of Pidotimod dry suspension and preparation method thereof |
| CN109771372A (en) * | 2019-03-26 | 2019-05-21 | 江苏四环生物制药有限公司 | A kind of dextromethorphan hydrobromide sustained-release suspension and preparation method thereof |
| CN111603456A (en) * | 2020-07-08 | 2020-09-01 | 江苏四环生物制药有限公司 | Carbixamine maleate controlled-release dry suspension and preparation method thereof |
| CN117017911A (en) * | 2023-08-15 | 2023-11-10 | 山东则正医药技术有限公司 | Dextromethorphan hydrobromide sustained-release suspension and preparation method thereof |
| CN117017911B (en) * | 2023-08-15 | 2024-06-07 | 山东则正医药技术有限公司 | Dextromethorphan hydrobromide sustained-release suspension and preparation method thereof |
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| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170721 |