CN101856354A - Novel composition for reducing blood sugar - Google Patents
Novel composition for reducing blood sugar Download PDFInfo
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- CN101856354A CN101856354A CN200910081690A CN200910081690A CN101856354A CN 101856354 A CN101856354 A CN 101856354A CN 200910081690 A CN200910081690 A CN 200910081690A CN 200910081690 A CN200910081690 A CN 200910081690A CN 101856354 A CN101856354 A CN 101856354A
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Abstract
The invention relates to a novel composition for reducing blood sugar, which is used for curing diabetes. The medicinal composition administrated through mucosae comprises Repaglinide serving as a primary medicament and other pharmaceutical excipients meeting physiological characteristics of the mucosae. The composition is characterized in that: the dose of the Repaglinide serving as the primary medicament is 0.5mg, 1mg, 2mg, or 4mg, and the composition is quickly absorbed by oral mucosae or nasal mucosae to act on the whole body.
Description
Technical field
The present invention relates to a kind for the treatment of diabetes that is used for, reduce the Pharmaceutical composition of blood glucose in the body fast, belong to the pharmaceutics field by mucosa delivery.
Background technology
Repaglinide is a kind of phthalamic acid derivant, and chemistry is by name: (S)-and 2-ethyoxyl-4-[2-[3-methyl isophthalic acid-[2-(piperidino) phenyl]-butane group]-amino]-2-carbonyl ethyl benzoic acid, structure is as follows:
Develop by Novo Nordisk company, went on the market through the FDA approval in 1997, can effectively control the blood glucose fluctuation after the type 2 diabetes mellitus patient has meal, simultaneously obviously reduced the severe hypoglycaemia incidence rate, overcome sulphur arteries and veins class medicine can not simulate insulin secretion pattern relevant the normal physiological state under (quick insulin secretion) with diet and cause time before the meal hypoglycemia and night hypoglycemic defective.The oral back of repaglinide the blood drug level peak occurred in about 1 hour, so need take before the meal, biology, availability was lower, amassed (AUC) below its maximal plasma concentration (Cmax) and plasma concentration one time graph to increase with dosage.Repaglinide mainly is by cytochrome P 45, is nonactive product at liver metabolism, 90% by bile excretion in feces, can be used for the patient of kidney merit damage, but hepatic insufficiency patient Ying Shen repaglinide.UKPDS studies show that in the treatment of type 2 diabetes mellitus, how can protect the function of islet cells as much as possible in good blood sugar control is exactly very important problem.Repaglinide is a kind of comparatively ideal medicine, and this medicine all goes on the market in global most countries at present, but dosage form is single, has only tablet over 10 years in clinical use.Because oral liver first-pass effect, the restriction that the patient of part hepatic insufficiency has been subjected to the use of this product.Mucosa delivery is compared with traditional oral administration, and convenient drug administration can stop at any time; Oral cavity and bronchia mucosal have abundant blood vessel, and medicine can directly enter body circulation by blood capillary, penetrate for medicine than skin is easier; Low enzymatic activity is avoided gastrointestinal enzyme and sour Degradation and liver first-pass effect.And mucosa absorption is rapid, and for the clinical treatment of diabetics, in time eliminating the acute complications that hyperglycemia causes is the vital task that improves patient's life quality, and as diabetic ketoacidosis and hyperosmolar nonketotic diabetic coma; Skin infection, upper respiratory tract infection, tuberculosis, acute complicationses such as urinary tract infection: and macroangiopathy: as coronary heart disease, ischemic or hemorrhagic apoplexy, renal arteriosclerosis, (lower limb are main in the limb artery sclerosis, show as lower limb pain, paraesthesia, intermittent claudication, extremity gangrene) etc. chronic complicating diseases has become the main cause that diabetes develop into human the 4th big dead disease, so mucoadhesive delivery system of exploitation quick acting, well replenish forgetting to take medicine and need as early as possible the patient of blood sugar lowering to be one, the selection of multi-pharmaceutics can be provided for the patient who is reluctant to swallow; And can give full play to fast, the biological utilisation characteristics high, easy to use of this dosage form absorption, eliminate diabetic complication harm as early as possible, improve clinical intervention therapeutic effect, be the clinical new formulation that this medicine is provided diabetes, increase medication compliance and biological effectiveness, improve drug level.This medicine Time To Market about ten years, but the exploitation of novel formulation report is few, Control Release magazines in 2005 have been reported the suspension microsphere of these product, at United States Patent (USP) 6878 in 2005, a kind of method for the treatment of diabetes is also disclosed in 749, comprising oral tablet, capsule and the suspension prescription of repaglinide.Because it is water insoluble that this pharmacology voltinism matter shows, cause its conventional tablet obviously to prolong dissolution time, take in the time of also can being subjected to eating food before the meal to the influence of medicine stripping, and the repaglinide polymorphic exists also outstanding to inhalation effects in the body, for preparation manufacture brings difficulty, the development of new preparation is necessary.
The present invention studies its mucoadhesive delivery system on the basis of existing technology, has obtained beyond thought effect.
Summary of the invention
Technical problem to be solved by this invention is the limitation that overcomes the existing preparation of repaglinide, develops a kind of preparation that passes through mucosa delivery of energy quick acting.
The main uses of said preparation is the treatment of type-II diabetes, and preferred form is a liquid form, can be drop or spray etc.
The repaglinide mucoadhesive delivery system comprises principal agent, solubilizing agent, absorption enhancer, pH regulator agent, adhesive agent, antiseptic, correctives etc.
Key technology of the present invention is to adopt the method that improves dissolubility in the present existing galenic pharmacy that the dissolubility of principal agent in different system studied; And according to the physiological characteristics in oral cavity, adjuvant and technology are screened, determined final prescription and technology.The solubilizing agent that it is good that the result shows solubilizing effect comprises cosolvent class such as ethanol, propylene glycol, glycerol, PEG200, PEG300, PEG400 and DMA etc., and its consumption is 20-50% (v/v); Surfactant-based as Tween 80, polysorbate60, polyoxyethylene castor oil, poloxamer etc., suitable amount ranges is 5-15% (w/v); Cosolvent and surfactant can use separately also respectively can unite use.
With the accumulation infiltration capacity is important indicator, and having set up with the sheep oral mucous membrane is the external absorption experiment method of animal model, estimates different absorption enhancers to the short effect of oozing of the saturating mucosa of repaglinide.Absorption enhancer has (1) cyclodextrin to comprise α, β, gamma-cyclodextrin, and the cyclodextrin of alkyl replacement: as methyl-beta-schardinger dextrin-, DM-, HP-etc.; Sulphur methyl ether beta-schardinger dextrin-, the malt-base beta-schardinger dextrin-; (2) cholic acid salt: glycocholate, cholate, deoxycholate, taurocholate, glucose cholate, CDC, bird rope deoxycholate etc.; (3) saturated or unsaturated fatty acid and ester thereof: as lauric acid, oleic acid, myristic acid, capric acid, laurate, caprylate, decanoin, cetylate, ethyl lactate; (4) alcohols: as propylene glycol, isopropyl alcohol, hexadecanol, lauryl alcohol, oleyl alcohol etc.; (5) ethers: polyoxyethylene laurel ether, polyoxyethylene octyl ether etc.; (6) sulfoxide class: as dodecyl methyl sulfoxide, dimethyl sulfoxide etc.; (7) lactams: the tall and erect ketone of dodecyl nitrogen, hold together the tall and erect ketone of cattle base nitrogen etc.; (9) ion-type, nonionic surfactant: as sodium lauryl sulphate, sad monoglyceride, Tween 80, span 20 etc.Above-mentioned absorption enhancer can singly be used or merge and use.Experiment finds that wherein the short effect of oozing of cyclodextrin and fatty acid and esters penetrating agent thereof is obvious, is preferred penetrating agent.With the cilium persistent movement time be index, by the Bufo siccus maxillary The effects that exsomatizes contain the mouth cilium toxicity of the repaglinide mucoadhesive delivery system of preferred penetrating agent.The result shows: 1. said preparation to ciliary movement without any influence; 2. preparation cilium toxicity is reversible, can recover swing behind the normal saline flushing, and mass motion time and normal saline are close.Illustrate that the preparation cilium toxicity that contains preferred penetrating agent is less, and the damage of cilium is had reversibility.The oral mucous membrane irritant experiment of new zealand white rabbit shows that said preparation is non-stimulated substantially to mucosa.Ooze effect and cilium toxicity for further estimating this absorption enhancer short under variable concentrations, and then determined the optimum amount of absorption enhancer, scope is at 3%-10%.
Also contain other adjuvant in the compositions of mucoadhesive delivery system, as antiseptic, thickening agent and pH buffer agent etc.
Antiseptic should not influence the physicochemical property of preparation, harmless in Mlc, nonirritant, the no special flavor of smelling.It is activating agent etc. that antiseptic commonly used has parabens, benzoic acid and salt thereof, sorbic acid, chlorobutanol, benzyl alcohol, phenethanol, thimerosal, chlorhexidine acetate and quaternary ammonium compound cationoid table, but the adding of discovering antiseptic all has in various degree influence to the physics of principal agent long term storage and chemical stability, and the sodium benzoate of selecting certain consumption at last is preferred antiseptic.
Thickening agent such as macromolecular compound: cellulose derivative such as carboxymethyl cellulose, hydroxypropyl cellulose etc. all can form the clathrate of medicine; Polyethylene glycols, polyvidone class etc. can form the solid dispersion of medicine, thereby help the absorption of medicine; Above-claimed cpd can be used for the adjusting of preparation toughness simultaneously, prolong drug and oral mucosal time of contact, improves bioavailability.This class material also has polyacrylic acid, polyvinyl alcohol, carbopol etc.
Studied the influence of the pH of solution on this basis again, selected best pH scope and best antiseptic consumption, thereby finished the formulation optimization of drug-supplying system, and carried out comprehensive and systematic research stability.In the pH buffer agent, citric acid buffer salt, acetate buffer salt, phosphate-buffered salt etc. are preferred.The pH scope can be 3.5-9, preferred 6-8.
The pharmacokinetics experimental result: 1,6 of male and female half and half beasle dogs are adopted in experiment, body weight 10～14kg, oral and the mouth mucosa drug administration of difference, subsequently in different time blood sampling 3ml, after blood sample is handled, measure blood drug level with the HPLC method of setting up, make two kinds of different way of administration blood drug level-time graphs, represent as Fig. 1 according to experimental result.It is fast that test finds that mouth mucosa drug administration absorbs than oral ordinary tablet, and the about 30min of average T max is faster more than 1 times than tablet, and significant difference is arranged; Through the bioequivalence analysis, the relative bioavailability of mouth mucosa drug administration improves 20% approximately.
2, adopt 6 of male and female half and half beasle dogs, body weight 10～14kg, oral and the nasal administration of difference, subsequently in different time blood sampling 3ml, after blood sample is handled, measure blood drug level with the HPLC method of setting up, make two kinds of different way of administration blood drug level-time graphs, represent as Fig. 2 according to experimental result.It is fast that test finds that nasal administration absorbs than oral ordinary tablet, and the about 13min of average T max accelerates infiltration rate greatly than tablet, and significant difference is arranged, and through the bioequivalence analysis, the relative bioavailability of mouth mucosa drug administration improves 16% approximately.
Description of drawings
Curve during average medicine after the oral and mouthful spray administration of Fig. 1 beasle dog
Curve during average medicine behind the oral and intranasal administration of Fig. 2 beasle dog
Blood glucose change curve behind two kinds of administrations of Fig. 3
Blood glucose change curve behind two kinds of administrations of Fig. 4
The specific embodiment
The present invention is further illustrated below in conjunction with the specific embodiment; it is not limitation of the invention; according to prior art well known in the art; embodiments of the present invention are not limited to this; therefore all this areas of making according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
Repaglinide 5g
Dehydrated alcohol 200ml
1,2-propylene glycol 200ml
Mentholum 0.5mg
Saccharin sodium 0.2mg
Phosphate buffer pH7-8 adds to 1000ml
Method for making: ethanol and repaglinide fully stirred evenly make whole dissolvings, add propylene glycol, Mentholum, saccharin sodium mixing again, add phosphate buffer to capacity at last and get final product.
By prescription and the prepared repaglinide oral spray of above embodiment 1, place 25,40 ℃ baking oven after the embedding respectively, respectively at the 1st, 2,3, the sampling in June, quicken and long-term stable experiment, the results are shown in Table 1,2.
Table 1 quickens (40 ℃) result of the test
The room temperature test that keeps sample for a long time
The table 2 room temperature result of the test that keeps sample for a long time
Embodiment 3
Get 6 of beasle dogs, double blinding, intersection, the administration of two cycles are divided into 2 groups at random by sex during experiment, 3/group.2 groups are respectively oral matched group and mouthful spray test group.Fasting 12h before the administration, during experiment, commercially available of one group of single oral dose repaglinide; The repaglinide spray of embodiment 1 is given in another group oral cavity, during the spray medicine, the beasle dog head is fixed, and makes oral cavity maintenance level, and medicine is quantitatively sprayed in the oral cavity, keeps flat-hand position more than 1 minute on the beasle dog head after the administration, in order to avoid medicinal liquid flows out.All will be arranged suitable blanking time after every kind of dosage form administration, to guarantee that enough blood sampling times are arranged, 2h can feed water and drink after the administration, but 3h feeding after the administration.Oral and mouthful spray administration before measurement fasting blood sugar of beasle dog, after the administration 8,13,25,35,60,75,90,120,180,240,360min is respectively at back leg vein measuring blood sugar of blood extracting value, time-the change of blood sugar curve sees Fig. 3.
Repaglinide 5g
Hydroxypropyl 0.1g
Ethanol 100ml
Macrogol 200 300ml
30 POVIDONE K 30 BP/USP 30 0.1g
Phosphate buffer pH6-7 adds to 1000ml
Method for making: the recipe quantity repaglinide is added ethanol dissolve clarification fully, add the PEG200 mixing again; Other adds in the medicinal liquid after getting appropriate amount of buffer solution and hydroxypropyl, 30 POVIDONE K 30 BP/USP 30 mixings, add at last buffer to full dose promptly.
Embodiment 5
Get 6 of beasle dogs, double blinding, intersection, the administration of two cycles are divided into 2 groups at random by sex during experiment, 3/group.2 groups are respectively oral matched group and nose spray test group.Fasting 12h before the administration, during experiment, commercially available of one group of single oral dose repaglinide; Another group nasal cavity is given the repaglinide spray of embodiment 4.All will be arranged suitable blanking time after every kind of dosage form administration, to guarantee that enough blood sampling times are arranged, 2h can feed water and drink after the administration, but 3h feeding after the administration.Oral and mouthful spray administration before measurement fasting blood sugar of beasle dog, after the administration 8,13,25,35,60,75,90,120,180,240,360min is respectively at back leg vein measuring blood sugar of blood extracting value, time-the change of blood sugar curve sees Fig. 4.
Embodiment 6
Repaglinide 5g
Ethanol 150ml
Tween 80 0.1g
PEG6000 0.1g
Saccharin sodium 0.5mg
Citric acid acid buffer pH7-8 adds to 1000ml
Method for making: the recipe quantity repaglinide is added ethanol dissolve clarification fully, add Tween 80, PEG6000 mixing again; Add at last buffer to full dose promptly.
Embodiment 7
Repaglinide 5g
Ethanol 100ml
Propylene glycol 400ml
Mentholum 0.5mg
Saccharin sodium 0.5mg
Phosphate buffer pH7-8 adds to 1000ml
Method for making: ethanol and repaglinide fully stirred evenly make whole dissolvings, add propylene glycol, Mentholum, saccharin sodium mixing again, add phosphate buffer to capacity at last and get final product.
Repaglinide 5g
Ethanol 100ml
Tween 80 0.05g
Propylene glycol 100mlg
HP-0.05g
Phosphate buffer pH6-8 adds to 1000ml
Method for making: the recipe quantity repaglinide is added ethanol dissolve clarification fully, add Tween 80, propylene glycol, HP-mixing again; Add at last buffer to full dose promptly.
The present invention is illustrated by above description and embodiment, for nonrestrictive, does not limit claim scope of the present invention.
Claims (10)
1. one kind is used for treating diabetes, by the Pharmaceutical composition of mucosa delivery, comprises that principal agent repaglinide and other meet the pharmaceutic adjuvant of mucosa physiological characteristics etc.
2. the repaglinide main dose specification is 0.5mg, 1mg or 2mg, 4mg in the Pharmaceutical composition according to claim 1, and said composition through port transmucosal or nasal membrane absorb performance general action rapidly.
3. the pharmaceutic adjuvant that meets the mucosa physiological characteristics in the Pharmaceutical composition of mucosa delivery according to claim 1 comprises that several mixing in absorption enhancer, solubilizing agent, pH regulator agent, adhesive agent, correctives, the antiseptic etc. are used.
4. the Pharmaceutical composition of mucosa delivery according to claim 1 liquid form preferably.
5. the Pharmaceutical composition of mucosa delivery according to claim 3, its described absorption enhancer has (1) cyclodextrin to comprise α, β, gamma-cyclodextrin, and the cyclodextrin of alkyl replacement: as methyl-beta-schardinger dextrin-, DM-, HP-etc.; Sulphur methyl ether beta-schardinger dextrin-, malt-base beta-schardinger dextrin-etc.; (2) saturated or unsaturated fatty acid and ester thereof: as lauric acid, oleic acid, myristic acid, capric acid, laurate, caprylate, decanoin, cetylate, ethyl lactate; (3) other: as sodium lauryl sulphate, sad monoglyceride, polyoxyethylene laurel ether etc., above-mentioned absorption enhancer can be singly with or merge and use.
6. described solubilizing agent comprises cosolvent class such as ethanol, propylene glycol, glycerol, PEG200, PEG300, PEG400 and DMA etc. according to claim 3, and is surfactant-based as Tween 80, polysorbate60, polyoxyethylene castor oil, poloxamer etc.
7. pH regulator agent according to claim 3 comprises as citric acid buffer salt, acetate buffer salt, phosphate-buffered salt etc.
8. adhesive agent according to claim 3 comprises the macromolecular compound class: cellulose derivative such as carboxymethyl cellulose, hydroxypropyl cellulose etc. all can form the clathrate of medicine; Polyethylene glycols, polyvidone class etc. can form the solid dispersion of medicine, thereby help the absorption of medicine; Above-claimed cpd can be used for the adjusting of preparation toughness simultaneously, the time of contact of prolong drug and mucosa, improves bioavailability.
9. correctives according to claim 3 comprises Herba Menthae, saccharin sodium, cyclamate etc.
10. antiseptic according to claim 3 should not influence the physicochemical property of preparation, harmless in Mlc, nonirritant, the no special flavor of smelling, and suitable antiseptic comprises sodium benzoate etc.
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| CN200910081690A CN101856354A (en) | 2009-04-09 | 2009-04-09 | Novel composition for reducing blood sugar |
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| CN200910081690A CN101856354A (en) | 2009-04-09 | 2009-04-09 | Novel composition for reducing blood sugar |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9656040B2 (en) | 2010-12-21 | 2017-05-23 | Koninklijke Philips N.V. | Active valve for ventilators |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9656040B2 (en) | 2010-12-21 | 2017-05-23 | Koninklijke Philips N.V. | Active valve for ventilators |
| US10589053B2 (en) | 2010-12-21 | 2020-03-17 | Koninklijke Philips N.V. | Active valve for ventilators |
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Open date: 20101013 |