CN100560058C - A kind of analgesic of oral, quick acting - Google Patents

Abstract

The present invention relates to comprise lornoxicam drug oral preparation, specifically provide a kind of oral, stable liquid lornoxicam preparation of specializing in gastrointestinal administration.It is the beneficial effect of onset and enhanced activity composition rapidly, and can be easily, without any the administration of uncomfortable ground.

Description

A kind of analgesic of oral, quick acting

Technical field

The present invention relates to comprise the oral formulations of lornoxicam medicine, specifically provide a kind of oral, stable liquid lornoxicam preparation of specializing in gastrointestinal administration.

Background technology

Lornoxicam is by the non_steroidal anti_inflammatory drug of Nycomed company exploitation, goes on the market in Denmark first in October, 1997.It suppresses the synthetic of prostaglandin (PGs) by the activity that suppresses Cycloxygenase.Analgesic such as the alternative morphine hydrochloride of clinical trial demonstration lornoxicam, pethidine hydrochloride and salt love song are many alleviate surgical patient's postoperative pain, can alleviate the pain of diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis effectively.

So far, have only the lornoxicam preparation of solid form to exist clinically, for example: tablet, freeze-dried powder.Because the character of lornoxicam is extremely unstable, comprise heat, light and oxygen.It is a kind of that CN97197619 provides, and lornoxicam and EDTA-2Na form salt, to increase its dissolubility, stability, reduces the method for turbidity.And CN02129254 forms complex to lornoxicam and nicotiamide, so that increase its dissolubility and stability.Though they can be prepared into the solution form, the two has emphasized it is aqueous solution simultaneously, and route of administration is " pharmaceutical composition that intestinal is outer or eye is suitable for ", illustrates that this class preparation is not suitable for oral.The two all fixes on acid-base value more than 7.5 in order to improve the stability of lornoxicam in aqueous solution, if it is oral to adopt this solution to be used for, the stimulating gastrointestinal road significantly reduces patient's toleration greatly.

Summary of the invention

The invention provides a kind of lornoxicam preparation of specializing in the liquid oral of gastrointestinal administration, it can significantly strengthen the beneficial effect of lornoxicam, than present commercially available prod remarkable stability and treatment advantage is arranged.Simultaneously, the invention provides a kind of selection, it provides a kind of new safety product as the substituting of prior art, and this dosage form will be that the doctor highly approves and puts forth effort and recommends.

The present invention has following characteristic: the invention provides the lornoxicam oral liquid, this liquid contains a large amount of edible oil.With oil is basement membrane, with unsettled, easily oxidized lornoxicam wraps up, and can avoid contacting of lornoxicam and oxygen; Contain a large amount of easily oxidation compositions in the oily substance simultaneously, play the effect of natural inhibitor, improve its stability greatly.And the medicine of this outer wrap oiliness basement membrane, have lipotropy, can pass fast in vivo and be fat-soluble cell membrane and enter cell interior, reach the purpose of quick inhibition of pain.Simultaneously, the employing oleaginous base is a carrier, can significantly improve the bioavailability of oral lornoxicam.The dispersibility of its height, good storing stability, the instability and the deterioration of preparation are suppressed.More advantageously be to have significantly improved the compliance of patient to treatment.

This product can select at present known any can be for oral liquid preparation form, as oral liquid (comprising oral solution, oral suspensions, Orally taken emulsion), drop, liquid hard capsule, soft capsule, spray, preferred soft capsule, this dosage form not only can have many advantages of soft capsule dosage form self, simultaneously for lornoxicam itself, also have than the more significant advantage of other oral liquids: compare with other dosage forms, soft capsule have bioavailability height, good airproof performance, content accurately, characteristics such as good looking appearance; For the patient, carry, take all very convenient; Can in capsule shell, add light screening material, overcome the shortcoming of lornoxicam photo-labile; Whole process of preparation need not heating, has overcome the instability of lornoxicam to heat.

Employing is that substrate also relatively is fit to the soft capsule dosage form among the present invention with the Polyethylene Glycol, comprises enclose.

To further make non restrictive description below to the present invention.

Active component:

By lornoxicam weight, every contains 0.5～50mg, preferred 1～25mg, more preferably 2～16mg.For the more effective dissolution rate that improves preparation that reaches, more advantageously active component is carried out pretreatment, it is crushed to more than 100 orders, more than preferred 120 orders, more preferably more than 180 orders, even micronization.

Substrate:

Through a large amount of experiment screenings, soft capsule mesostroma of the present invention is preferably vegetable oil, comprise pharmaceutical grade salad oil, soybean oil, oil with hydrogenated soybean, Oleum Arachidis hypogaeae semen, Semen Maydis oil, Oleum sesami, olive oil or their mixed system, to account for the total restatement of content, its consumption is 50-99%, preferred 70-97%, more preferably 80-95%.

This liquid exists with the solution situation, also can be suspension, emulsion etc.According to the existence form difference, should add suitable cosolvent, suspending agent and emulsifying agent, be selected from tween 80, Arlacel-60, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, pluronic, poloxamer, MCT Oil, tristerin, Cera Flava, haze tallow, spermaceti, insect wax, Cera Flava, rice bran wax, sugarcane wax, hydrogenated palm oil, Oleum Cocois, hydrogenated coconut oil, lecithin, hydrolecithin, fabaceous lecithin, hydrogenated soybean lecithin or their mixed system, preferred tween 80, Arlacel-60, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, pluronic, poloxamer, glyceryl monostearate, Cera Flava, haze tallow, Cera Flava, hydrogenated palm oil, Oleum Cocois, hydrogenated coconut oil, lecithin, hydrolecithin, fabaceous lecithin, hydrogenated soybean lecithin or their mixed system, more preferably tween 80, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Cera Flava, hydrogenated palm oil, hydrogenated coconut oil, lecithin, fabaceous lecithin or their mixed system; To account for the total restatement of content, its consumption is 2-30%, preferred 3-15%, more preferably 4-10%.

For further improving the quality of products, add stabilizing agent, antioxidant and antiseptic again in the solution; Stabilizing agent comprises glycerol, propylene glycol, triglyceride, or their mixed system.Preferably glycerine, propylene glycol or their mixed system.To account for the total restatement of content, its consumption is 2-30%, preferred 3-15%, more preferably 4-10%.

Antioxidant comprises various vitriolic sodium salts, BHA, and vitamin E, EDTA-2Na, EDTA-CaNa, to account for the total restatement of content, its consumption is 0.05-15%, preferred 0.5-10%, more preferably 1-5%.。

The present oral soft capsule that the someone hints or clearly instruction comprises lornoxicam and other active component simultaneously as yet clinically.The invention provides this technology, successfully in the lornoxicam soft capsule, added other active component, for example tiopronin, tranquilizer (stable, clozapine, chlorpromazine etc.), other nonsteroidal anti-inflammatory drugs, analgesic (as: morphine, tramadol, caffeine, lignocaine, tetracaine), aspirin, antibacterial-anti-inflammatory drug, Chinese medicine extract or its extract active component etc., to improve the curative effect of lornoxicam, and/or overcome untoward reaction behind the oral lornoxicam, and/or reach synergism.

Soft capsule material of the present invention is advisable with suitable elasticity, comprise sizing material and solvent, sizing material comprises plant gum and animal glue, as: arabic gum, carrageenin, xanthan gum, Algin, starch (derivant that comprises starch deep processed product or starch) glue, glutinous rice foxtail millet (Oryza glutinosa), foxtail millet corn, gelatin etc., preferred gelatin; General selection water is solvent;

For solving soft capsule poor stability, leakage and the slow shortcoming of disintegrate, the present invention takes selected sizing material control viscosity, iron-holder and kinetic parameter reached the purpose of strict screening capsule material.

In addition, aldehyde material and gelatin autoxidation process all can make gelatin take place crosslinked and influence disintegrate, for overcoming these influence factors, adopt to add an amount of plasticizer in the capsule material, through a large amount of tests, have successfully overcome the defective of above-mentioned soft capsule.Wherein plasticizer comprises glycerol, xylitol, sorbitol (acid anhydride), dimethicone, propylene glycol, Polyethylene Glycol, cyclodextrin, starch (derivant that comprises starch deep processed product or starch) class, various acid etc., preferably glycerine, Polyethylene Glycol, sorbitol (acid anhydride), tartaric acid, glycine.For making capsule more stable and sensation is better, can in glue, add an amount of antiseptic, antioxidant, opacifier, aromatic and pigment etc.

The present invention does not make specific limited to the preparation method of soft capsule, can adopt this area conventional method, for example pressing or dropping preparation method (drop pill method).The face shaping of described soft capsule is not made specific limited, can be existing arbitrary shape.

Following examples are intended to further specify the present invention, scope of the present invention are not limited.Those skilled in the art can not depart from the improvement and the variation of category of the present invention and spirit to embodiment disclosed herein.

Embodiment 1

Prescription

Constituent content (mg/ capsule/grain)

Chlorine promise battalion health 5

Propylene glycol 20

Oleum Arachidis hypogaeae semen 150

Fabaceous lecithin 20

Vitamin E 5

Amount to 200

Technology:

Get the lornoxicam raw material, pulverize, behind 200 mesh sieves, standby excessively.

Get recipe quantity propylene glycol and vitamin E, behind the mix homogeneously, add the lornoxicam of above-mentioned standby recipe quantity, dispersed with stirring evenly after, add the Oleum Arachidis hypogaeae semen of recipe quantity, after stirring, add fabaceous lecithin, after stirring, be processed into soft capsule

Embodiment 2

Prescription

Constituent content (mg/ capsule/grain)

Lornoxicam 2

Glycerol 20

Semen Maydis oil 400

Lecithin 20

Sodium sulfite 8

Amount to 450

Technology:

Get chlorine promise battalion health raw material, pulverize, behind 120 mesh sieves, standby excessively.

Get recipe quantity glycerol and sodium sulfite, after mix homogeneously and the dissolving, add the lornoxicam of recipe quantity, after dispersed with stirring is even, add the Semen Maydis oil of standby recipe quantity, after stirring, add lecithin, after stirring, be processed into soft capsule

Embodiment 3

Prescription

Constituent content (mg/ capsule/grain)

Lornoxicam 8

Glycerol 50

Triglyceride 20

Salad oil: soybean oil=1: 1 500

Hydrogenated palm oil 15

Cera Flava 8

Sodium pyrosulfite 7

Amount to 608

Technology:

Get the lornoxicam raw material, pulverize, behind 180 mesh sieves, standby excessively.

Get recipe quantity glycerol, triglyceride and sodium pyrosulfite, after mix homogeneously and the dissolving, the lornoxicam that adds standby recipe quantity, after dispersed with stirring is even, add the salad oil of recipe quantity and the miscella of soybean oil, after stirring, add Cera Flava and hydrogenated palm oil, after stirring, be processed into soft capsule

Embodiment 4

Constituent content (mg/ capsule/grain)

Lornoxicam 4

Propylene glycol 41

Polyoxyethylene hydrogenated Oleum Ricini 20

Tween 80 30

Semen Maydis oil: Oleum Sesami=3: 1 350

EDTA-CaNa 10

Amount to 455

Technology:

Get the lornoxicam raw material, pulverize, behind 280 mesh sieves, standby excessively.

Get recipe quantity polyoxyethylene hydrogenated Oleum Ricini and EDTA-CaNa, add above-mentioned lornoxicam, after disperseing fully, add propylene glycol and tween 80, be stirred well to dissolving fully, add the prior Semen Maydis oil of synthetic recipe quantity in proportion and the miscella of Oleum Sesami, after stirring, be processed into soft capsule.

Embodiment 5:

Prescription

Constituent content (mg/ capsule/grain)

Lornoxicam 3

Clozapine 5

Tween 80 40

Glycerol 80

Oleum Arachidis hypogaeae semen 300

Hydrolecithin 30

BHA 20

Amount to 478

Technology

Get lornoxicam and clozapine raw material, pulverize, behind 200 mesh sieves, standby excessively.

Get recipe quantity glycerol, add above-mentioned lornoxicam and clozapine, after being uniformly dispersed, add tween 80, be stirred well to fully, add Oleum Arachidis hypogaeae semen, hydrogenated palm oil and BHA, after stirring, be processed into soft capsule.

Embodiment 6:

Prescription

Constituent content (mg/ capsule/grain)

Lornoxicam 4

Semen Maydis oil 300

Fabaceous lecithin 15

BHA 6

Amount to 325

Technology

Get the lornoxicam raw material, pulverize, behind 200 mesh sieves, standby excessively.

Get the recipe quantity Semen Maydis oil, lecithin, BHA is stirred well to fully and is uniformly dispersed, and adds above-mentioned lornoxicam raw material, after stirring, is processed into soft capsule.

Embodiment 7:

Prescription

Constituent content (mg/ capsule/grain)

Lornoxicam 8

Salad oil 300

Glyceryl monostearate 13

Hydrogenated coconut oil 20

Lecithin 15

EDTA-2Na 6

Sodium pyrosulfite 5

Amount to 367

Technology

Get lornoxicam, sodium pyrosulfite and EDTA-2Na supplementary material are pulverized, and be behind 200 mesh sieves, standby excessively.

Get the recipe quantity salad oil, glyceryl monostearate, hydrogenated coconut oil, lecithin adds above-mentioned lornoxicam and sodium pyrosulfite and EDTA-2Na, after being uniformly dispersed, be stirred well to fully after, be processed into soft capsule.

Embodiment 8:

Prescription

Constituent content (mg/ capsule/grain)

Lornoxicam 8

Soybean oil 300

Cera Flava 11

Hydrogenated palm oil 18

Soybean phospholipid 10

EDTA-2Na 8

Sodium pyrosulfite 7

Amount to 362

Technology

Get lornoxicam, sodium pyrosulfite and EDTA-2Na supplementary material are pulverized, and be behind 120 mesh sieves, standby excessively.

Get the recipe quantity soybean oil, Cera Flava, hydrogenated palm oil, soybean phospholipid adds above-mentioned lornoxicam and sodium pyrosulfite and EDTA-2Na, after being uniformly dispersed, be stirred well to fully after, be processed into soft capsule.

Claims (10)

1, a kind of soft capsule comprises lornoxicam and oleaginous base, and wherein by lornoxicam weight, each preparation unit contains 0.5～50mg; Oleaginous base is a vegetable oil, and to account for the total restatement of content, its consumption is 50-99%.

2, the described soft capsule of claim 1, wherein by lornoxicam weight, each preparation unit contains 1～25mg.

3, the described soft capsule of claim 1, wherein by lornoxicam weight, each preparation unit contains 2～16mg.

4, the described soft capsule of claim 1, vegetable oil wherein are pharmaceutical grade soybean oil, oil with hydrogenated soybean, Oleum Arachidis hypogaeae semen, Semen Maydis oil, Oleum sesami, olive oil or their mixed system.

5, the described soft capsule of claim 1, lornoxicam wherein is crushed to more than 100 orders at least as active component.

6, the described soft capsule of claim 1, lornoxicam wherein is crushed to more than 120 orders at least as active component.

7, the described soft capsule of claim 1, lornoxicam wherein is crushed to more than 180 orders at least as active component.

8, the described soft capsule of claim 1, lornoxicam wherein is crushed to micronization as active component.

9, the described soft capsule of claim 1, oleaginous base wherein is to account for the total restatement of content, and its consumption is 70-97%.

10, the described soft capsule of claim 9, oleaginous base wherein is to account for the total restatement of content, and its consumption is 80-95%.