CN101658487B - Glimepiride aqueous solution administration system and preparation method thereof - Google Patents
Glimepiride aqueous solution administration system and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a glimepiride aqueous solution administration system and a preparation method thereof, which belong to the technical field of medicaments. A glimepiride aqueous solution preparation consists of an active component glimepiride and a pharmaceutically acceptable adjuvant, and each 100 milliliters of the preparation contains 0.1 to 10 grams of the glimepiride, preferably 0.1 to 5 grams, and most preferably 0.1 to 2 grams. The glimepiride aqueous solution administration system and the preparation method have the advantages of successfully solving the problem that the glimepiride is extremely difficult to dissolve, and greatly improving the stability of a solution through a series of prescription screening works. The system or a composition performs administration in a sublingual spraying mode to avoid the action of alimentary canals, the reactions of gastrointestinal tracts and the liver first pass effect; besides, the system or the composition has quick response and high bioavailability, is particularly suitable for controlling the postprandial blood sugar, and can be used for treating the type 2 diabetes which cannot be appropriately controlled by dietary restriction and sports. The system or the composition also has the following advantages that: the use is convenient, the dosage can be adjusted as required, the compliance is good, the system or the composition is particularly suitable for old people and the patients who cannot swallow conveniently, the preparation process is simple and practicable and is suitable for industrial production, and the like.
Description
Technical field
The present invention relates to glimepiride aqueous solution administration system and preparation method thereof, preferred undertongue spraying agent belongs to medical technical field.
Background technology
Diabetes are by chronic metabolism disorder diseases of general such as the relative or absolute not enough caused sugar of insulin in the body, fat, protein, originally asymptomatic for a long time, occur in blood sugar increasing and the urine sugar being arranged later on, show what is called " three-many-one-little " symptom (being that polydipsia, polyuria, polyphagia and health are become thin) clinically, as can not long term maintenance blood glucose near normal level, the pathological changes of histoorgans such as easy concurrent cardiovascular, kidney, retina, nerve, skin and disable or cause death.The 5th IDF's meeting once pointed out, whole world type 2 diabetes mellitus patient has after diagnosing reached 1.3 hundred million people at present, type 2 diabetes mellitus will be popular in developing countries such as China, India 21 century, by 2025, whole world diabetics will break through 300,000,000, and China's diabetics sum will become the country of the number of diabetics in the world more than second that is only second to India near 100,000,000.China is in economic relatively advanced areas such as Beijing at present, and urban district resident's onset diabetes rate has been higher than 5.3%.Along with improving constantly of China's living standards of the people, the sickness rate of diabetes also will continue to improve, and therefore the medicine of exploitation prevention and treatment diabetes will have very huge social and economic benefit.Sulfonylurea drugs can be by promoting insulin secretion with the special acceptor interaction of β cell surface.Its hypoglycemic activity extensively is considered as the non-fat type 2 diabetes mellitus patient's of moderate a line hypoglycemic drug certainly.
Glimepiride (glimepiride) (chemical name: 1-[4-(3-ethyl-4-methyl-2-oxo-3-pyrrolin-1-formamido)-ethyl]-benzene sulfonamido]-3-(trans-4-methyl cyclohexyl) urea) be the medicine that German Hoechst MarionRoussel company develops, be the medicine under the French Sanofi-Aventis (Sanofi-Aventis) now.Nineteen ninety-five takes the lead in Sweden's listing, and commodity are called Amaryl (Ya Moli), and check and approve in the U.S. by FDA and go on the market November 30 nineteen ninety-five.It is the long-acting oral hypoglycemic of sulfonylurea of new generation of treatment non-insulin-dependent diabetes mellitus (NIDDM), its blood sugar reducing function mainly is to stimulate the beta Cell of islet excreting insulin, part improves the sensitivity of surrounding tissue to insulin, has the outer blood sugar reducing function of pancreas simultaneously again.According to the literature, its hypoglycemic activity onset is fast than glipizide, combine with Insulin receptor INSR and dissociated speed faster than glibenclamide, lessly cause heavier hypoglycemia, administration 0.5mg/d promptly effectively.Glimepiride can be used to keep on a diet, take exercise invalid patient separately, also can use with other antidiabetic drugs or insulin compatibility, has advantages such as efficient, long-acting, safety, low dosage, hypotoxicity, adverse effect are few.Its chemical structural formula is as follows:
Glimepiride is white or off-white color crystalline powder, and odorless is tasteless, 205～209 ℃ of fusing points dissolve in chloroform, soluble,very slightly in ethanol, almost insoluble or insoluble in water, almost insoluble or insoluble in the 0.1mol/L hydrochloric acid solution, soluble,very slightly in the 0.1mol/L sodium hydroxide solution.From the character of crude drug, the dissolubility of raw material in various media is all less.Glimepiride clothes back reached blood medicine peak value in 2～3 hours, and oral 4mg average peak is about 300ng/ml, about 5～8 hours of t1/2, and this product is metabolized to the metabolite of no hypoglycemic activity through the P450 oxide in liver, and 60% through homaluria, and 40% through defecate.The common initial dose of administration: treatment stage in the early stage, the initial dose of glimepiride be 1～2mg once a day, administration during dinner during breakfast or for the first time.Those patients to the antidiabetic drug sensitivity should begin once a day with 1mg, and should careful adjustment dosage.There is not the accurate dose relation between glimepiride and other oral antidiabetic drug.The maximum predose of glimepiride is no more than 2mg.Usually maintenance dose: usually maintenance dose be 1～4mg once a day, the maximum maintenance dose of recommendation be 6mg once a day.After dosage reached 2mg, the increase of dosage was according to patient's change of blood sugar, and per 1～2 weekly dose raises and is no more than 2mg.
The present preparation of glimepiride is solid preparations such as tablet, (soft) capsule and dispersible tablet, and the stripping of medicine and absorption are subjected to certain restriction.
United States Patent (USP) (patent No. 4379785) shows that its preparation comprises glimepiride and/or its esters treatment diabetes that can be taken orally, its dosage form is a tablet, comprises common carrier and adjuvant as Pulvis Talci, starch, lactose or magnesium stearate.This patent also demonstrates and uses activated substrate and/or meticulous discrete form is useful, but it does not provide any details about the substrate of its use good bioavailability to be arranged.
European patent (patent No. 0 649 660) is the non-water-soluble pharmaceutical preparation about intestinal canal administration, comprises the method for producing glimepiride.The preparation that its is described comprises can tolerate on water-insoluble and/or lipophilic medium and one or more physiology water miscible or with micelle state amphoteric surfactant soluble in water.
International patent application (patent No. WO2007/072218 A2) is about a kind of new recipe ingredient and dosage unit and the glimepiride that particle diameter is very fine and/or the preparation of its salt.This patent is thought can influence the dissolubility and the bioavailability of medicine by the particle diameter that changes crude drug.
This patent of Chinese patent (publication number CN1739493A) relates to the new pharmaceutical preparation of glimepiride (dispersive glimepiride tablet) and prescription is formed, and its preparation method.But this method still can not well solve the problem that stripping reaches poor solubility slowly, and preparation dispersible tablet process is numerous and diverse.
This patent of Chinese patent (publication number CN1709242A) relates to a kind of Glime piride soft capsule and preparation method thereof, though this method makes glimepiride become solution-type, suspension type, but main additives such as the lytic agent of its use, cosolvent are organic solvent and vegetable and animals oils, the adding of organic solvent not only also can increase production cost to the person is unhelpful.
Summary of the invention
First technical problem that the present invention will solve is to overcome problems such as poor stability, dissolution and the bioavailability of existing glimepiride solid orally ingestible is low, a kind of bioavailability height, rapid-action, steady quality is provided, has the glimepiride solution drug-supplying system of good blood sugar reducing function.
Another technical problem that the present invention will solve provides a kind of simple glimepiride buccal delivery system preparation method.
For achieving the above object, the present invention is by the following technical solutions:
A kind of glimepiride aqueous solution preparation is made up of active component glimepiride and pharmacy acceptable auxiliary, contains glimepiride 0.1-10g in every 100ml preparation, preferred 0.1-5g, most preferably 0.1-2g.
Contained component and content thereof are as follows in described every 100ml preparation, and surplus is a water:
Glimepiride 0.1-10g
Cosolvent 0.1-20g
Stabilizing agent 0.05-10g.
Also contain in the following component one or more in described every 100ml preparation, contained component and content thereof are as follows, and surplus is a water:
Antiseptic 20-30ml (liquid) or 0.001-0.003g (solid)
Surfactant 0.1-2g
Correctives 0.025-20g
Absorption enhancer 0.001-50g
Antioxidant 0.01-0.25g.
Described cosolvent is one or more in diethylamine, nicotiamide, meglumine, ethylenediamine, acetamide, ethanolamine, monoethanolamine, carbamide or other aliphatic amine.Preferred acetamide or meglumine; Contain cosolvent 0.1-20g in every 100ml preparation, preferred 0.2-20g, more preferably 0.4-15g.
Described stabilizing agent is a Tween 80, poloxamer, the cyclodextrin that the cyclodextrin of α, β, gamma-cyclodextrin, alkyl replace is as methyl-beta-schardinger dextrin-, DM-, HP-etc., sulphur methyl ether beta-schardinger dextrin-, the malt-base beta-schardinger dextrin-; Preferred HP-contains stabilizing agent 0.05-10g in every 100ml preparation, preferred 0.1-5g.
Described surfactant is one or more in sodium lauryl sulphate, sad monoglyceride, Tween 80, polysorbate60, span 20, the Brij; The preferred Tween 80 of surfactant contains surfactant 0.1-10g in every 100ml preparation, preferred 0.1-5g, more preferably 0.1-2g.
Described antiseptic is one or more in benzalkonium bromide, benzalkonium chloride, ethanol, ethyl hydroxybenzoate, parabens, benzoic acid and salt thereof, sorbic acid, chlorobutanol, benzyl alcohol, phenethanol, thimerosal, glycerol, chlorhexidine acetate and the quaternary ammonium compound cationoid surfactant; Antiseptic preferably glycerine or ethanol contain antiseptic 20-30ml in every 100ml preparation, preferred 20ml.
Described absorption enhancer is cyclodextrin, and the cyclodextrin that replaces of alkyl of α, β, gamma-cyclodextrin, as methyl-beta-schardinger dextrin-, DM-, HP-etc., sulphur methyl ether beta-schardinger dextrin-, the malt-base beta-schardinger dextrin-, cholic acid salt, lauric acid, ethyl lactate, propylene glycol, lauryl alcohol, dimethyl sulfoxide, the tall and erect ketone of dodecyl nitrogen, poloxamer 188, poloxamer 237, poloxamer 338; The preferred poloxamer 188 of absorption enhancer contains absorption enhancer 0.001-50g in every 100ml preparation, preferred 0.01-30g, most preferably 0.1-10g.
Described correctives is stevioside, saccharin sodium, sorbitol, xylitol, maltose alcohol, Aspartane, Mentholum etc.; The preferred stevioside of correctives, xylitol, Mentholum or Aspartane; Contain correctives 0.025-20g in every 100ml preparation, preferred 0.025-15g.
Described antioxidant is sodium sulfite, sodium sulfite, Polymeric sodium metaphosphate., sodium thiosulfate, sodium pyrosulfite, sodium ascorbate; The preferred sodium thiosulfate of antioxidant contains antioxidant 0.01-0.25g in every 100ml preparation, preferred 0.05-0.2g.
Described preparation is spray, oral liquid, syrup or other liquid preparations.
Described glimepiride drug-supplying system is the liquid drug-supplying system, the dosage form of preferred sublingual administration.
According to the present invention, the dosage form of sublingual administration has drop, aerosol, spray, gel, microsphere and Emulsion etc.Consider the convenience of medication, the feasibility of suitability for industrialized production and the characteristics of above-mentioned dosage form, the preferred undertongue spraying agent of the present invention.
Glimepiride undertongue spraying agent of the present invention makes by being prepared as follows method: get glimepiride, add cosolvent, the back adds the water that accounts for cumulative volume 70%, after ultrasonic about 20 minutes, with 70 ± 10 ℃ of heating in water bath to being transparency liquid, after add successively a kind of in absorption enhancer, stabilizing agent, antiseptic, correctives, antioxidant, the surfactant or (with) multiple; Add water to full dose at last, after solution was mixed into clear, component was packed into and is promptly got product in the multiple dose administration container under aseptic condition.
Because after glimepiride was water-soluble, stability of solution was relatively poor, infers only 1.3 years its effect duration by classical constant temperature test, is unsuitable for producing, transports and stores.So carried out Study on Stability work.In the prescription screening process, by investigating a series of stabilizing agent and/or antioxidant, finally determined a kind of stabilizing agent/or antioxidant make the stability of solution be significantly improved, classical constant temperature test infers that its effect duration is about 11 years.
Advantage of the present invention is: the preferred glimepiride of the present invention is as the active component in the solution drug-supplying system, successfully solved the extremely insoluble problem of glimepiride, this system or compositions are by the Sprayable administration, can avoid digestive tract effect and liver first-pass effect, and have rapid-action, bioavailability is high, be specially adapted to the control of post-prandial glycemia, can be used for the treatment of the type 2 diabetes mellitus that diet control and motion still can not suitably control.Also have easy to use, dosage can be adjusted as required, compliance is good, is particularly suitable for old people and the patient that is not easy to swallow.And preparation technology's simple possible is fit to advantages such as suitability for industrialized production.
The invention will be further described below in conjunction with better embodiment, is not limitation of the present invention, and the replacement that is equal to of all any this areas of doing according to the disclosure of invention all belongs to protection scope of the present invention.
The specific embodiment
Embodiment 1: the glimepiride undertongue spraying agent
One. component:
Glimepiride 10g
Tween 80 6g
Meglumine 45g
Poloxamer 188 2g
HP-1g
Glycerol 200ml
Stevioside 0.4g
Redistilled water adds to 1000ml
Two. preparation method:
Earlier respectively glimepiride and meglumine are crossed 100 mesh sieves, earlier glimepiride is mixed with the meglumine of recipe quantity, add suitable quantity of water, after ultrasonic about 20 minutes, after 70 ± 10 ℃ of heating in water bath are dissolved to settled solution, the Tween 80, poloxamer 188, glycerol, HP-, the stevioside that add recipe quantity successively respectively, add an amount of redistilled water, behind the ultrasonic mix homogeneously, add water to 1000ml, filter then, canned, seal, pack, being up to the standards is finished product.
Embodiment 2: the glimepiride undertongue spraying agent
One. component:
Glimepiride 10g
Meglumine 25g
Tween 80 6g
HP-1g
Glycerol 200ml
Aspartane 0.4g
Redistilled water adds to 1000ml
Two. preparation method:
Earlier respectively glimepiride and meglumine are crossed 100 mesh sieves, earlier glimepiride is mixed with the meglumine of recipe quantity, add suitable quantity of water, after ultrasonic about 20 minutes, after 70 ± 10 ℃ of heating in water bath are dissolved to settled solution, the Tween 80, glycerol, HP-, the Aspartane that add recipe quantity successively respectively, add an amount of redistilled water, behind the ultrasonic mix homogeneously, add water to 1000ml, filter then, canned, seal, pack, being up to the standards is finished product.
Embodiment 3: the glimepiride undertongue spraying agent
One. component:
Glimepiride 10g
Meglumine 50g
Tween 80 10g
HP-1g
Ethanol 200ml
Stevioside 1g
Redistilled water adds to 1000ml
Two. preparation method:
Earlier respectively glimepiride and meglumine are crossed 100 mesh sieves, earlier glimepiride is mixed with the meglumine of recipe quantity, add suitable quantity of water, after ultrasonic about 20 minutes, after 70 ± 10 ℃ of heating in water bath are dissolved to settled solution, the Tween 80, ethanol, HP-, the stevioside that add recipe quantity successively respectively, add an amount of redistilled water, behind the ultrasonic mix homogeneously, add water to 1000ml, filter then, canned, seal, pack, being up to the standards is finished product.
Embodiment 4: the glimepiride undertongue spraying agent
One. component:
Glimepiride 10g
Meglumine 45g
HP-1g
Glycerol 200ml
Stevioside 0.4g
Redistilled water adds to 1000ml
Two. preparation method:
Earlier respectively glimepiride and meglumine are crossed 100 mesh sieves, earlier with glimepiride with add suitable quantity of water again after the meglumine of recipe quantity mixes, ultrasonic about 20 minutes, in 70 ± 10 ℃ of water-baths and heating for dissolving to settled solution, add glycerol, HP-, the stevioside of recipe quantity successively respectively, add an amount of redistilled water, behind the ultrasonic mix homogeneously, add water to 1000ml, filter then, canned, seal, pack, being up to the standards is finished product.
Embodiment 5: the glimepiride undertongue spraying agent
One. component:
Glimepiride 10g
Meglumine 30g
Sodium thiosulfate 2g
HP-1g
Glycerol 200ml
Xylitol 15g
Mentholum 0.5g
Redistilled water adds to 1000ml
Two. preparation method:
Earlier respectively glimepiride and meglumine are crossed 100 mesh sieves, earlier with glimepiride with add suitable quantity of water again after the meglumine of recipe quantity mixes, heating for dissolving is to settled solution in ultrasonic about 20 minutes and 70 ± 10 ℃ of water-baths, the sodium thiosulfate, xylitol, the HP-that add recipe quantity successively respectively, add an amount of redistilled water, in addition glycerol is mixed the back dative with Mentholum and be listed as U.S. urea solution mixing, behind the mix homogeneously, add water to 1000ml, filter then, canned, seal, pack, being up to the standards is finished product.
Embodiment 6: the glimepiride undertongue spraying agent
One. component:
Glimepiride 10g
Meglumine 40g
HP-30g
Ethanol 200ml
Xylitol 15g
Mentholum 0.5g
Redistilled water adds to 1000ml
Two. preparation method:
Earlier respectively glimepiride and meglumine are crossed 100 mesh sieves, earlier with glimepiride with add suitable quantity of water again after the meglumine of recipe quantity mixes, after also 70 ± 10 ℃ of heating in water bath were dissolved to settled solution in ultrasonic about 20 minutes, the HP-, the xylitol that add recipe quantity successively respectively, add an amount of redistilled water, in addition ethanol is mixed the back dative with Mentholum and be listed as U.S. urea solution mixing, behind the ultrasonic mix homogeneously, add water to 1000ml, filter then, canned, seal, pack, being up to the standards is finished product.
Embodiment 7: the glimepiride undertongue spraying agent
One. component:
Glimepiride 1g
Meglumine 1g
HP-1g
Glycerol 300ml
Tween 80 1g
Xylitol 15g
Mentholum 0.5g
Poloxamer 188 1g
Sodium thiosulfate 0.5g
Redistilled water adds to 1000ml
Two. preparation method:
Earlier respectively glimepiride and meglumine are crossed 100 mesh sieves, earlier glimepiride is mixed with the meglumine of recipe quantity, add suitable quantity of water, after ultrasonic about 20 minutes, after 70 ± 10 ℃ of heating in water bath are dissolved to settled solution, the Tween 80, HP-, sodium thiosulfate, the xylitol that add recipe quantity successively respectively, poloxamer 188, add an amount of redistilled water, in addition glycerol is mixed the back dative with Mentholum and be listed as U.S. urea solution mixing, behind the ultrasonic mix homogeneously, add water to 1000ml, filter then, canned, seal, pack, being up to the standards is finished product.
Embodiment 8: the glimepiride undertongue spraying agent
One. component:
Glimepiride 100g
Meglumine 200g
HP-10g
Glycerol 300ml
Tween 80 20g
Xylitol 150g
Mentholum 5g
Poloxamer 188 100g
Sodium thiosulfate 2.5g
Redistilled water adds to 1000ml
Two. preparation method:
Earlier respectively glimepiride and meglumine are crossed 100 mesh sieves, earlier glimepiride is mixed with the meglumine of recipe quantity, add suitable quantity of water, after ultrasonic about 20 minutes, after 70 ± 10 ℃ of heating in water bath are dissolved to settled solution, the Tween 80, HP-, sodium thiosulfate, the xylitol that add recipe quantity successively respectively, poloxamer 188, add an amount of redistilled water, in addition glycerol is mixed the back dative with Mentholum and be listed as U.S. urea solution mixing, behind the ultrasonic mix homogeneously, add water to 1000ml, filter then, canned, seal, pack, being up to the standards is finished product.
Embodiment 9: preparation is to oral cavity mucosa irritation experiment
The present invention has carried out the toxicity of the above embodiment of stripped Bufo siccus maxillary The effects 1,2,3,4 glimepiride sublingual administration systems, and dosage is that every Bufo siccus gives 1 spray (100 microlitre/spray), administration in continuous 7 days, the pathological section of making maxillary.
The result shows that said preparation toxicity is reversible, and toxicity is less.The Bufo siccus maxillary experiment of exsomatizing shows that said preparation is very little to mucous membrane irritation.
Embodiment 10: pharmacokinetics and bioavailability experiment
One. material and method:
1. medicine: according to the preparation of embodiment 5 methods preparation
2. method: 6 beasle dogs, male, body weight 10～12kg, adopt binary cycle intersection own control experimental design, comparing embodiment 4 preparation sublingual administrations (every 2mg) and common comparison film oral (every 2mg, glimepiride tablet, Shanghai Tiancifu Biological Engineering Co., Ltd., lot number 071202) pharmacokinetics is calculated absolute bioavailability.Before two kinds of preparation administrations and after the administration 0.5,1.0,2.0,2.5,3.0,4.0,6.0,9.0,11.0,24.0 and 48.0h, respectively from foreleg venous blood collection 3mL, put in the test tube that heparin handled, the centrifugal 10min of 3000rpm, gemfibrozil are interior mark.Adopt liquid chromatography-tandem mass spectrometry (LC/MS/MS) method to measure blood drug level.
Two. the result:
Concrete measurement result sees Table 1:
Table 1: main pharmacokinetic parameter and bioavailability behind beasle dog glimepiride sublingual administration and the oral administration
The result shows: behind sublingual spraying administration of beasle dog glimepiride and the oral administration, its body giving drugs into nose all meets two chamber models for dynamic process, and tmax is respectively 2.41 ± 0.86h and 6.36 ± 1.65h.The sublingual spraying administration absorbs very fast.The relative bioavailability of sublingual spraying drug-delivery preparation is greater than 100%.
Embodiment 11: classical constant temperature experiment
Because glimepiride aqueous solution instability so need to add one or more stabilizing agents to improve its stability, is estimated stabilizer function by classical constant temperature test.
One. material and method:
1. material: according to the preparation (1) of embodiment 5 methods preparation with according to the preparation of removing sodium thiosulfate (2) of embodiment 5 methods preparation.
2. method: get preparation (1) and preparation (2) sample solution respectively,, get the subsequent filtrate fill in the 2mL ampoule with 0.45 μ m filtering with microporous membrane, sealing by fusing, place respectively in 70,80,90 and 100 ℃ the constant temperature oven, each temperature is by the EXPERIMENTAL DESIGN time, take out 2 ampoules respectively, cessation reaction in the water-bath is behind the solution mixing at every turn, be mixed with need testing solution, sample introduction 20 μ L measure content.
Two. the result: the result is shown in the following table.
Table 2: the glimepiride solution decomposition data that does not contain/contain stabilizing agent
Table 3: do not contain regression equation and decomposition rate constant under the glimepiride solution different temperatures of stabilizing agent
According to Arrhenius exponential law: 1gK=-E/2.303RT+1gA, with 1gK 1/T is made linear regression, get regression equation: 1gK=-5330.5/T+12.829, | r|=0.9879.Decomposition rate constant K and the effect duration of calculating room temperature (25 ℃) thus are: K
25 ℃=8.7382 * 10
-6h
-1, t
0.9 25 ℃=1.37 years.
Table 4: contain regression equation and decomposition rate constant under the glimepiride solution different temperatures of stabilizing agent
According to Arrhenius exponential law: 1gK=-E/2.303RT+1gA, with 1gK 1/T is made linear regression, get regression equation: 1gK=-6195.5/T+14.806, | r|=0.9839.Decomposition rate constant K and the effect duration of calculating room temperature (25 ℃) thus are: K
25 ℃=1.03688 * 10
-6h
-1, t
0.9 25 ℃=11.6 years.
As seen from the experiment, the glimepiride stability of solution of adding stabilizing agent is higher than the glimepiride solution that does not add stabilizing agent far away.
Embodiment 12: influence factor's test
One. material and method
1. material: according to the preparation (lot number: 080407) of embodiment 5 methods preparation
2. method:
(1) strong illumination test
To this product sample (lot number: 080407) shone 10 days, took a sample to check in 0,5,10 day with being placed on behind the ampoule fusion sealing under 4500 ± 500LX illumination.
(2) hot test
To this product sample (lot number: 080407) placed 10 days, took a sample to check in 0,5,10 day with being placed on behind the ampoule fusion sealing in 60 ℃ of isoperibols.
(3) accelerated test
Prepare 3 batch samples (pressing the method preparation of embodiment 5), be positioned over 40 ℃, the RH75% condition is investigated each index after following 3 months.
Two. the result
(1) strong illumination test: the results are shown in Table 5.
Table 5: strong illumination test
(2) high temperature experiment: the results are shown in Table 6.
Table 6: hot test
(3) accelerated test the results are shown in Table 7.
Table 7: accelerated test result
The new pharmaceutical preparation that the invention provides a kind of glimepiride is the glimepiride spray, and its preparation method is provided.The present invention adopts certain water miscible cosolvent to make glimepiride reach higher dissolubility in water, solved the problem of glimepiride indissoluble, make it can reach 20mg/mL to the dissolubility in water by insoluble in water, so can improve the stripping of this insoluble drug greatly and shorten peak time, also have laid a good foundation for other liquid preparations of this medicine of preparation.
Claims (10)
1. glimepiride undertongue spraying agent, it is characterized in that: contained component and content thereof are as follows in described every 100ml preparation, and surplus is a water:
Described cosolvent is a meglumine;
Described stabilizing agent is a HP-;
Described surfactant is a Tween 80;
Described antiseptic is glycerol or ethanol;
Described absorption enhancer is a poloxamer 188;
Described correctives is stevioside, saccharin sodium, sorbitol, xylitol, maltose alcohol, Aspartane or Mentholum;
Described antioxidant is sodium sulfite, sodium sulfite, Polymeric sodium metaphosphate., sodium thiosulfate, sodium pyrosulfite or sodium ascorbate.
2. glimepiride undertongue spraying agent according to claim 1 is characterized in that: contain cosolvent 0.2-20g in described every 100ml preparation.
3. glimepiride undertongue spraying agent according to claim 1 is characterized in that: contain cosolvent 0.4-15g in described every 100ml preparation.
4. glimepiride undertongue spraying agent according to claim 1 is characterized in that: contain stabilizing agent 0.1-5g in described every 100ml preparation.
5. glimepiride undertongue spraying agent according to claim 1 is characterized in that: contain antiseptic 20ml in described every 100ml preparation.
6. glimepiride undertongue spraying agent according to claim 1 is characterized in that: contain absorption enhancer 0.01-30g in described every 100ml preparation.
7. glimepiride undertongue spraying agent according to claim 1 is characterized in that: contain absorption enhancer 0.1-10g in described every 100ml preparation.
8. glimepiride undertongue spraying agent according to claim 1 is characterized in that: contain correctives 0.025-15g in described every 100ml preparation.
9. glimepiride undertongue spraying agent according to claim 1 is characterized in that: described antioxidant is sodium thiosulfate, contains antioxidant 0.05-0.2g in every 100ml preparation.
10. the preparation method of any one the described glimepiride undertongue spraying agent among the claim 1-9, it is characterized in that: get glimepiride, add cosolvent, the back adds the water that accounts for cumulative volume 70%, after ultrasonic 20 minutes, with 70 ± 10 ℃ of heating in water bath to being transparency liquid, after add absorption enhancer, stabilizing agent, antiseptic, correctives, antioxidant and surfactant successively; Add water to full dose at last, after solution was mixed into clear, component was packed into and is promptly got product in the multiple dose administration container under aseptic condition.
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| CN108210501B (en) * | 2016-12-14 | 2019-03-08 | 中国人民解放军军事医学科学院毒物药物研究所 | A kind of medicinal composition for injections of sulfonylureas and preparation method thereof |
| CN112028807A (en) * | 2020-08-07 | 2020-12-04 | 重庆康刻尔制药股份有限公司 | Refining method of glimepiride bulk drug |
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| US6559187B2 (en) * | 2000-08-07 | 2003-05-06 | Ranbaxy Signature Llc | Liquid formulation of metformin |
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| US6962691B1 (en) * | 1999-05-20 | 2005-11-08 | U & I Pharmaceuticals Ltd. | Topical spray compositions |
| US6559187B2 (en) * | 2000-08-07 | 2003-05-06 | Ranbaxy Signature Llc | Liquid formulation of metformin |
| CN1785188A (en) * | 2005-10-08 | 2006-06-14 | 贵州神奇集团控股有限公司 | Compounding metformin glipidide prepn. for treating diabetes type II, and its prepn. method |
| CN101181278A (en) * | 2007-11-19 | 2008-05-21 | 北京诚创康韵医药科技有限公司 | Pharmaceutical composition containing glucosamine |
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| CN101658487A (en) | 2010-03-03 |
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