CN1290525A - Freeze dried zhalaipulong instant oral composition - Google Patents

Abstract

The present invention relates to a freeze dried composite which may be taken orally and can be dissolved in mouth fast. The composite contains Zhalaipulong or its medicinally acceptable solvate and salt and one or more kinds of medicinally acceptable supplementary material. The present invention also describes the preparation process and clinical application of the composite.

Description

Cryodesiccated zhalaipulong instant oral composition

The present invention relates to a kind of pharmaceutical composition, a kind of specifically oral instant pharmaceutical composition that supplies that uses the Freeze Drying Technique preparation.The effective ingredient that said composition comprises is N-[3-(3-cyano pyrazole [1, a 5-a] pyrimidin-7-yl) phenyl]-N-ethyl-ethamine, general Zaleplon by name.This structural formula of compound can be expressed from the next:

Zaleplon structure involved in the present invention is different from traditional hypnotic (benzene diaza class, barbiturates and known other hypnotic), it is the short-acting hypnotic of a kind of BZ1 of acting on (ω 1) receptor, it optionally acts on the ω site of benzene phenodiazine in the brain-GABA receptor complex a subunit, thus performance sleep effect.Its human body half-life is 1 hour only, and the back metabolism rapidly of taking medicine replaces normal natural sleep, has therefore farthest eliminated late effect next day that hypnotic often had.Test shows, takes Zaleplon and withdraws no withdrawal symptoms after 12 months, shows patient's no dependence, interrupts taking the bounce-back that Zaleplon 4 Zhou Houwei cause insomnia.Compare at present clinical employed most of sleeping pill selectivitys with it relatively poor or metabolism is slower, and show clinical withdrawal symptoms.

In Europe, the U.S. and Canada surpass 3700 routine patients' (comprise 65-85 year gerontal patient) clinical trial certificate: Zaleplon is helping the patient to keep the natural sleep state aspect evident in efficacy.

Find under study for action, although various traditional oral Pharmaceutical dosage forms such as existence such as tablet, capsule and pill are arranged, but these Orally administered composition forms have shortcoming separately, especially concerning the gerontal patient and can not swallow or the patient that is reluctant to swallow, the consideration of dosage form design is still insufficient.With regard to traditional tablet and capsule, the more weak patient of gerontal patient or swallow complaint is difficult to swallow or often produces the sensation in " being stuck in " throat and cause discomfort, and these compositionss pass through the process of disintegrate and stripping in vivo mostly, and general onset is slower.Need not in powder and the granule body through disintegrating procedue, but its mouthfeel is bad, takes inconvenience, and unrestrained easily and cause dosage inaccurate when unpacking.Taking these oral solid formulations in addition needs great quantity of water drinking, and (before sleeping) then can cause patient's compliance to descend under should not the great quantity of water drinking environment.Liquid oral compositions such as syrup etc. are easy to take relatively, but can not expect then that for most of gerontal patients being difficult to measure volume required patient can take by correct dosage.Therefore society wishes to have taking convenience very much, and onset is rapid, acts on stable pharmaceutical composition.

The problems referred to above that appear as of using the oral instant compositions of freeze-drying method preparation provide a solution.For example Chinese patent NO 1140408,1085081,1140407; Described in British patent NO 1548022,2111423,2119246,2114440,2111184,2120370 and the United States Patent (USP) NO 5046618,5188825, list herein and briefly introduce.

The end of the seventies, Britain Weyth company at first is applied in the Freeze Drying Technique of injection on the oral formulations, oral freeze-dried compositions begins one's study, the eighties, Xie Le company participated in exploitation, the efficient suitability for industrialized production of primary study has the freeze-dried composition of a plurality of medicines to apply for a patent or produce listing at present.

Oral freeze-dried compositions is to adopt vacuum freezing drying method production, and generally included for three steps: 1 freezes: medicinal liquid is placed mould, be refrigerated to fully solidify, molding; 2 sublimation dryings: moisture is separated with solute with methods such as decompression, intensifications; 3 packings.

Oral instant can dissolve rapidly in 5-15s in the oral cavity and not need the water assisting deglutition, only can finish with several swallowing acts and take medicine, very convenient.What oral formulations was removed situation in clinostatism volunteer esophagus comparison shows that ordinary tablet and capsule move slower in esophagus, oral instant and is not had trapping phenomena then owing to can collapse the dissolving of loosing rapidly in esophagus, so more convenient practicality.

In animal body and the test of oral instant of carrying out in the human body pharmacokinetics also show, oral instant absorb than ordinary tablet fast, the blood drug level height, bioavailability is good, can reduce dosage.It is big that the oral fast solubility preparation has also overcome the suppository absorption difference, though injection absorbs the shortcoming of fast administration inconvenience, it absorbs fast, and taking convenience and onset are rapid.

In addition, γ-flicker labelling method is to oral instant, chewable tablet and liquid preparation show that in gastric retention time mucosal coating The Characteristic Study oral instant retention time at gastric obviously is longer than conventional tablet and liquid preparation, and be also even than chewable tablet in the distribution of gastric mucosa.

In the process of the oral instant compositions of the cryodesiccated Zaleplon of research, we find, Zaleplon is different with other drug, it is difficult in the water and disperses, and dispersion is very unstable, and the divided dose of well-known oral freeze-dried instant oral composition is based on the volume of inserting the mould herb liquid or quality, and the instability of Zaleplon dispersion directly can influence the amount of the every contained Zaleplon of finished product.

We find to adopt following several mode to address this problem now: the micronized Zaleplon of 1 employing is a raw material; 2 add the surfactant of proper proportion; 3 add the stability that suspending agent can further improve disperse system.

Therefore the present invention at first provides a kind of for oral instant freeze-dried composition, and said composition comprises Zaleplon or the receptible derivant of its medicine, one or more surfactants, one or more suspending agents.

Term " instant " is meant according to disclosed method among the British patent No1548022, and be 60 seconds or shorter the disintegration of solid dosage forms in 37 ℃ of water, preferred 5-10 second or shorter time.

As described in above-mentioned patent, owing to said composition need exist with solid form, and should guarantee its mouldability, be beneficial to the production and the packing of product; The existence of framework material has simultaneously guaranteed the porous status spongiosus of instant compositions, can rapid osmotic compositions be dissolved rapidly when making water touch instant compositions, so said composition can comprise the skeletal substance of the acceptable water miscible or water dispersible of a series of medicines to compositions inside.Suitable framework material comprises, the mixture of gelatin (gelatin that comprises partial hydrolysis), polysaccharide or gelatin polysaccharide, preferably gelatin hydrolysate.

For keeping said composition hardness, said composition can comprise suitable filler, suitable filler comprises preferably polyhydric alcohol of polyhydric alcohol (as mannitol, sorbitol and xylitol etc.) sugar (sucrose, glucose, lactose and maltose etc.), because of its compositions has preferably mouthfeel and has better physical character.

Though Zaleplon is water-soluble hardly, still need add an amount of flavoring agent and cover its bitter taste, available flavoring agent can comprise spicing agent (as Fructus Fragariae Ananssae, Herba Menthae, Fructus Pruni pseudocerasi, peach flavor essence etc.); The mixture of sweet taste flavoring agent (as aspartame etc.) and other flavoring agents (as citric acid etc.) or several flavoring agents.

The oral instant compositions of the cryodesiccated Zaleplon of the present invention adopts the classical way preparation described in the above-mentioned patent.

The oral freeze-dried compositions of Zaleplon is to adopt vacuum freezing drying method production, comprises for four steps altogether: the preparation of 1 suspension: micronized Zaleplon is added surfactant and disperse medium an amount of, smash to pieces and be uniformly dispersed; 2 freeze: with the Zaleplon dispersion liquid by volume divided dose place mould, be refrigerated to fully rapidly solidify, molding; 3 sublimation dryings are removed moisture to being lower than 5%; 4 press molds packing.

In preparation suspension process, the suspension solution of Zaleplon is extremely unstable and make final product medicament contg inequality, and the method that the present invention relates to can address this problem.

During drug suspension, the option table surface-active agent adds in the solvent for use in preparation, the method that adopts tissue to smash to pieces, and homodisperse, thereby guaranteed the homogeneity of unit dose Chinese medicine content.The surfactant that is suitable for can comprise tween, span and poloxamer and composition thereof.Preferred surfactants is the mixture of Tween 80 and sorbester p18 (1: 1).

Production cycle is longer, adds the stability that suspending agent can further increase suspension, and suitable suspending agent can comprise polyvinylpyrrolidone, cellulose family, carbomer or their mixture, preferably polyvinylpyrrolidone.

The present invention relates to the mold volumes size and take from the size and the shape of Zaleplon tablet.The WO94/12142 suggestion has provided the preferred mold materials of mold, and we adopt preferred blister pack bag.With automatic filling means the required dosage suspension is inserted mold.

The present invention prepares the oral instant compositions of Zaleplon with freeze-drying.In freeze drying chamber, decompression down makes Zaleplon suspension solution coagulation forming in the mould with freeze-drying, removes moisture, under the 0.1-1.0 millibar dry 180-500 minute.

Packaging material the present invention adopts pressure sensitive adhesion cover material on the mold materials around the depression, preferred aluminium foil of coverage rate or lamination aluminium foil.Covering mould can be adhered on the mold materials by the same manner.

Be used to form the solvent preferred water of pharmaceutically active substance suspension, also can sneak into cosolvent such as ethanol if desired.

The suspension that the present invention relates to has also comprised supplementary elements such as preservative agent, flavoring agent, coloring agent, sweeting agent, filler and composition thereof.Used preservative agent is a benzoate, and flavoring agent is the Fructus Pruni pseudocerasi flavoring agent, and selected sweeting agent is an aspartame, and filler is a mannitol.These usual excipients can be improved the physical property of peroral dosage form.

The oral instant compositions of cryodesiccated Zaleplon provided by the invention, the content of its Zaleplon is between 1mg-20mg.

The invention provides a kind of method for the treatment of human insomnia disease, this method comprises the oral instant compositions of Zaleplon of taking a kind of freeze-drying method preparation to the patient.

Following non-limiting example will the present invention will be further described.

Embodiment 1:

Zaleplon 5.0mg

(mean diameter is less than 50 μ m)

Gelatin 5.5mg

Mannitol 4.1mg

Aspartame 0.75mg

Cherry flavor 0.30mg

Tween 80 0.50mg

Sorbester p18 0.50mg

Pure water adds to 0.3ml

This compositions can adopt following method preparation.

1 adds gelatin in the entry and to soak dissolving, adds the Tween 80 sorbester p18 and is stirred to dissolving, adds Zaleplon and disperses with refiner, adds other adjuvant mix homogeneously.

2 with the suspension divided dose in blister pack.

3 freezing drying under reduced pressure to moisture less than 5%.

4 press molds packing.

1 suspension of writing out a prescription has obvious layering after 1 hour in placing, and requires to place mould and quick freezing molding at once after the preparation, to prevent the layering of Zaleplon suspension.

Embodiment 2:

Zaleplon 5.0mg

Gelatin 5.5mg

Mannitol 4.1mg

Polyvinylpyrrolidone 2.6mg

Aspartame 0.75mg

Cherry flavor 0.30mg

Tween 80 0.50mg

Sorbester p18 0.50mg

Pure water adds to 0.3ml

Preparation method is with prescription 1.

Prescription 2 increases polyvinylpyrrolidone on prescription 1 basis makes the Zaleplon suspension stable in 6 hours, is more suitable for suitability for industrialized production.

Claims (8)

1. one kind can supply oral instant freeze-dried composition, and said composition comprises Zaleplon or the receptible derivant of its medicine, one or more surfactants, the receptible excipient of one or more medicines.

2. the compositions of claim 1, said composition contains one or more suspending agents.

3. claim 1 or 2 compositions, the said composition outward appearance is a tablet.

4. the compositions of claim 1-3, said composition comprises into the Zaleplon of salt form.

5. the compositions of any one requirement among the claim 1-4, wherein sweeting agent comprises mannitol.

6. the compositions of any one requirement among the claim 1-4, wherein the content of Zaleplon is 1mg-50mg.

7. the compositions of any one claim among the claim 1-6, said composition comprises Zaleplon, gelatin, mannitol, flavoring agent.

8. the method for a Cure for insomnia, this method comprises the compositions of using any one claim among the claim 1-7 to the patient.