CN1847230A - Cinnarizine water-soluble salt and its injection form - Google Patents

Abstract

The present invention is one kind of water soluble cinnarizine salt and its injection form, and the water soluble cinnarizine salt has high water solubility and capacity of entering blood directly. The water soluble cinnarizine salt is prepared with cinnarizine and one or several kinds of inorganic acid or organic acid in the molar ratio of 1 to 1 and through reaction. It is further prepared into abacterial powder for injection or abactereial injection. The present invention can produce treating effect fast and enter blood-brain barrier, and has fast acting and small dosage.

Description

CN water-soluble salt and injection type thereof

Technical field

The injection type that the present invention relates to a kind of CN water-soluble salt and make by its water-soluble salt.

Background technology:

CN (midronal) is the piperazines calcium antagonist.This product is the piperazines calcium-channel antagonists, can stop stream in the calcium of vascular smooth muscle, causes vasodilation and improves cerebral circulation and coronary artery circulation, especially the cerebrovascular is had certain selective action, and surrounding blood vessel is also had dilating effect.Vaso-excitor materials such as histamine, serotonin, bradykinin, suprarenin, norepinephrine, Angiotensin had antagonistic action.This product can suppress PDE, stop cAMP resolve into 5 of non-activity '-AMP, thereby increase intracellular cAMP concentration, suppress histamine, serotonin, the release of multiple biologically active substance such as bradykinin also has restraining effect to the activation of complement C4.Be used for cerebral thrombosis, cerebral embolism, cerebral arteriosclerosis, hematencephalon decubation, subarachnoid hemorrhage decubation, cerebral trauma sequela, auditory vertigo, coronary sclerosis and because the bad treatments such as disease that cause of tip circulation.Relevant in recent years bibliographical information, this product can be used for chronic urticaria, anaphylaxis dermatosis such as geroderma itch.The existing listing formulation of this product is tablet, capsule at present, and bioavailability is lower.The formulation of developing has injection.But, when the preparation injection, have to adopt special means because of this product solubleness in water is very low.The normal at present method that adopts has two kinds, and a kind of is to add tensio-active agent Tween-80 in the preparation, reaches by solubilising and satisfies clinical purpose of answering, but still cannot say for sure not separate out when card is in adding transfusion; Tween-80 has certain safety issue when being used for intravenous administration in addition.Simultaneously also can run into problems during assay.Another kind method is to adopt the method for hydroxypropyl inclusion, but there is the problem of the excessive and security hidden danger of supplementary product consumption in the injection of this method preparation, though hydroxypropyl (levonorgestrel) has good water-solubility and solubilizing effect, up to the present FDA has only ratified the long-acting subcutaneous implant of Itraconazole injection and Levonorgestrel (Jadelle  Implants) and has used hydroxypropyl.The powder injection that uses hydroxypropyl to make does not add mixed solvents such as ethanol, propylene glycol in prescription, the pungency of blood vessel is improved significantly, and this is to use the advantage of this auxiliary material uniqueness.But just because of a large amount of hydroxypropyls that use, we it be unclear that the existence form of its solubilizing mechanism, inside and outside and the internal metabolism behavior of medicine and auxiliary material, though the pharmacological toxicology of existing animal test and documents and materials show, this auxiliary material security can guarantee substantially, but to different medicines, its indication, usage and dosage, treatment time and cycle are different, with regard to the security in treatment clinical course difficult of proof of existing declaration material.Use a large amount of hydroxypropyls to be solubilizing agent in the prescription, solubilizing mechanism may be that medicine passes through hydrogen bond or Intermolecular Forces and hydroxypropyl beta cyclodextrin formation inclusion compound, or medicine and auxiliary material combine with intermolecular weak bond and form coordination compound (super molecular compound), and the solvability that causes medicine greatly for a change.Pass hemato encephalic barrier but whether the medicine of the medicine of some indication such as central nervous system is influenced medicine because of deliquescent change, change in the body of medicine and distribute, and then influence result of treatment.

Summary of the invention

The purpose of this invention is to provide a kind of injection type that is directly used in the CN water-soluble salt of intravenously administrable.This salt and injection type thereof are to can not also using with the patient of oral medicine.The inventor considers, because CN has two nitrogen in its molecular structure, therefore the alkalescence that salient pole is weak might make one mole the CN and the various strong acid reactions of equivalent, can make it become soluble salt.Here said equivalent is for residue carboxyl in the organic acid.And medicine directly enters blood during owing to injection, therefore can bring into play therapeutic action rapidly, can fully be absorbed by living organism again, all is being much better than existing CN oral dosage form aspect instant effect and low-consuming two.Thereby, the invention provides a kind of CN water-soluble salt, it is characterized in that it is formed by CN and the mineral acid that pharmaceutically allows, any or the two reaction in the organic acid.Said acid will be done suitable selection among the present invention, it must be mineral acid, the organic acid that pharmaceutically allows, and it wants to generate with CN and have enough water miscible salt, and the PH of the aqueous solution of its formation simultaneously is moderate, so just can guarantee that contained CN is not damaged.In addition, formed salt also will be easy to disengage CN in the aqueous solution, can bring into play drug effect rapidly and fully to guarantee it.Said organic acid preferred example has: formic acid, acetate, propionic acid, butyric acid, lactic acid, hydroxybutyric acid, oxysuccinic acid, tartrate, citric acid, lactic acid, toxilic acid, fumaric acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, how sulfonic acid, triolefin sulfonic acid, succsinic acid, camphorsulfonic acid, taurine.It also can be any mixture more than 2 kinds in them.Said mineral acid has hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or Hydrogen bromide.In addition, the present invention also provides a kind of CN water needle injection, it is characterized in that, the aqueous injection that the aqueous solution that it is formed by above-mentioned CN water-soluble salt and water makes, with and through lyophilize and the powder injection type made.The above-mentioned aqueous solution can be that CN and organic acid react in water and the aqueous solution of the CN water-soluble salt that directly forms, also can be again that it is the soluble in water and aqueous solution that forms after obtaining the water-soluble fluidity salt of CN.In the aqueous solution that forms by CN water-soluble salt of the present invention, store at normal temperatures and do not separate out solid, and composition is still stable.Usually must be made into the injection type of proper concn and proper volume with physiological saline.Yet according to the present invention, the preferably aqueous solution freeze-drying of the CN water-soluble salt that will generate through reaction and make powder injection, from several respects such as storage, transportation and uses bigger benefit is arranged all like this, the water of injection specified amount faces with preceding as long as promptly can be used for injection or add in the intravenous infusion using after the thixotropy.Also the salt that forms can be added poly(oxyethylene glycol) 400 or propylene glycol and water for injection and make injection liquid.

Compare with the CN oral preparation of prior art, the invention has the beneficial effects as follows: the good water solubility of medicine, and, therefore can bring into play therapeutic action rapidly because medicine directly enters blood, do not influence again and enter hemato encephalic barrier, all playing more significant effect aspect instant effect and low-consuming two.Enumerate embodiment below the embodiment and further explain the present invention, but be not subjected to the restriction of these examples.

Embodiment 1

With the 0.01mol CN, 0.01mol lactic acid and 30ml water add in the 100ml vial, at room temperature stir 10 minutes raw materials and dissolve rapidly, and gained solution is water white transparency, and the pH value that records solution with pH meter is 3.8.The gained salts solution is under reduced pressure concentrated, move in the plate then and place in moisture eliminator, allow it fling to moisture, become transparent glass shape solid behind the branch that anhydrates, continue placement again and allow moisture volatilize fully, gradually become white solid, the product that obtains weighs 4.2.This product is the water-soluble salt of CN of the present invention.Add 30ml water in this solid and stir with glass stick, within one minute, solid i.e. all dissolvings.Solution is by predetermined solubility dilute with water, and through Sterile Filtration, the peace of packing under aseptic condition bottle sealing by fusing had both got aqueous injection; Be sub-packed in freeze-drying in the vial by predetermined dose in addition, promptly obtain powder needle injection of the present invention.Face water, can use after the thixotropy with preceding adding predetermined amount.

Embodiment 2

With the 0.01mol CN, 0.005mol methylsulfonic acid and 30ml water add in the 100ml vial, at room temperature stir 10 minutes raw materials and dissolve rapidly, and gained solution is water white transparency, and the pH value that records solution with pH meter is 4.0.The gained salts solution is under reduced pressure concentrated, move in the plate then and in moisture eliminator, place, allow it fling to moisture, become transparent glass shape solid behind the branch that anhydrates, continue placement again and allow moisture volatilize fully, gradually become white solid, the product that obtains heavily about 3.8.This product is the property salt of CN of the present invention.Add 30ml water in this solid and stir with glass stick, within one minute, solid i.e. all dissolvings.Solution is by predetermined solubility dilute with water, and through Sterile Filtration, the peace of packing under aseptic condition bottle sealing by fusing had both got aqueous injection; Be sub-packed in the flat middle freeze-drying of glass by predetermined dose in addition, promptly obtain powder needle injection of the present invention.Face water, can use after the thixotropy with preceding adding predetermined amount.

Embodiment 3

With the 0.01mol CN, 0.005mol hydrochloric acid and 30ml water add in the 100ml vial, at room temperature stir 10 minutes raw materials and dissolve rapidly, and gained solution is water white transparency, and the pH value that records solution with pH meter is 2.5.The gained salts solution is under reduced pressure concentrated, move in the plate then and place in moisture eliminator, allow it fling to moisture, become transparent glass shape solid behind the branch that anhydrates, continue placement again and allow moisture volatilize fully, gradually become white solid, the product that obtains weighs 3.5.This product is the water-soluble salt of CN of the present invention.Add 30ml water in this solid and stir with glass stick, within one minute, solid i.e. all dissolvings.Solution is by predetermined solubility dilute with water, and through Sterile Filtration, the peace of packing under aseptic condition bottle sealing by fusing had both got aqueous injection; Be sub-packed in freeze-drying in the vial by predetermined dose in addition, promptly obtain powder needle injection of the present invention.Face water, can use after the thixotropy with preceding adding predetermined amount.

Embodiment 4

Prescription: hydrochloric acid CN (in CN) 20g

Hydrochloric acid is transferred pH 2.5

Poly(oxyethylene glycol) 400 500ml

Water for injection 10000ml

Get the hydrochloric acid CN and add polyoxyethylene glycol 400, it is an amount of to add the injection water, makes dissolving, adds hydrochloric acid and transfers pH2.5, add 0.5g pin carbon, 80 ℃ were stirred 10 minutes, filtered, and crossed 0.22 μ m millipore filtration, after-teeming is penetrated water to full dose, and embedding is in the 10ml ampoule, and 10ml/ props up, promptly.

Embodiment 5

Prescription: hydrochloric acid CN (in CN) 20g

N.F,USP MANNITOL 100g

Hydrochloric acid is transferred pH 2.5

Water for injection 10000ml

Getting hydrochloric acid CN and N.F,USP MANNITOL, to add the injection water an amount of, makes dissolving, adds hydrochloric acid and transfer pH2.5, adds 0.5g pin carbon, 80 ℃ were stirred 10 minutes, filtered, and crossed 0.22 μ m millipore filtration, and after-teeming is penetrated water to full dose, can is in 20ml control small jar, and 10ml/ props up, the well-established law lyophilize, promptly.

Claims (8)

1. The water-soluble salt of cinnarizine is characterized in that: it is formed by 1:1 molar reaction of cinnarizine and any one or both of the inorganic acids and organic acids allowed in medicine. 2. The water-soluble salt of cinnarizine according to claim 1, characterized in that: said inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or hydrobromic acid. 3. The water-soluble salt of cinnarizine according to claim 1, characterized in that: formic acid, acetic acid, propionic acid, butyric acid, lactic acid, hydroxybutyric acid, malic acid, tartaric acid, lemon Acid, lactic acid, maleic acid, fumaric acid, sulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trienesulfonic acid, succinic acid, camphorsulfonic acid, taurine One or any mixture of two or more. 4. An injection form of a water-soluble salt of cinnarizine, characterized in that it is a sterile powder for injection made of a water-soluble salt of cinnarizine, and the sterile powder includes freeze-dried preparations or solution-type injections. 5. The injection form of cinnarizine water-soluble salt according to claim 4, characterized in that: it is made from water-soluble cinnarizine salt through solvent crystallization or freeze-drying, or it is made from water-soluble cinnarizine salt plus Freeze-dried product made of appropriate amount of excipients. 6. The injection form of cinnarizine water-soluble salt according to claim 4, characterized in that: said solution-type injection or sterile powder for injection prepared by freeze-drying method contains additives of co-solvent and pH regulator . 7. The injection form of the water-soluble salt of cinnarizine according to claim 6, wherein the co-solvent is selected from polyethylene glycol 400, Tween-80, and 1,2-propanediol. 8. The injection form of water-soluble salt of cinnarizine according to claim 4, characterized in that: the injection contains water-soluble salt of cinnarizine equivalent to 5-60 mg of cinnarizine, and 1,2-propanediol is used as a cosolvent , water is a solvent, hydrochloric acid is a pH regulator, and the pH is adjusted to 2.5.