CN103159636A

CN103159636A - Aminomethyl caproic acid derivative and use

Info

Publication number: CN103159636A
Application number: CN2013101155310A
Authority: CN
Inventors: 李兴惠
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-04-05
Filing date: 2013-04-05
Publication date: 2013-06-19
Anticipated expiration: 2033-04-05
Also published as: CN103159636B

Abstract

The invention discloses an aminomethyl caproic acid derivative and use, in particular a composition which comprises a compound shown by formula I and a compound shown by formula II as an impurity. The invention further discloses a medical preparation prepared by the composition and pharmaceutical use thereof. The compound provided by the invention has good pharmaceutical properties.

Description

Aminomethyl caproic acid derivative and purposes

Technical field

The present invention relates to can be used for aminomethyl caproic acid derivative (S)-3-(the aminomethyl)-5-methylhexanoic acid particularly of the assisting therapy of generalized anxiety disorder, diabetic peripheral neurophaty, postherpetic neuralgia, fibromyalgia syndrome, epilepsy, with and uses thereof.

Background technology

(S)-3-(aminomethyl)-5-methylhexanoic acid, general Prey Bahrain by name (pregabalin) also often is called lyrica, and its molecular formula is C ₈H ₁₇NO ₂, molecular weight is 159.23.It is the same with gabapentin, and Prey Bahrain is that 3 of a kind of γ-aminobutyric acid (GABA) replace analogues, and their chemical structural formula is as follows:

Prey Bahrain GABA gabapentin

Prey Bahrain (pregabalin by Pfizer's exploitation, trade(brand)name Le Ruika, Lyrica) be a kind of 3 replacement analogues of γ-aminobutyric acid, it had obtained related compound and the expection adoption person thereof of the antiepileptic drug gabapentin (gabapentin) of huge business success already as the said firm.Prey Bahrain is neuralgia medicine of new generation, agents of calcium ion channel modulators.By the neurone of accommodative excess excitement, reduce the excessive release of excitatory neurotransmitter, be used for the treatment of the neurogenic pains such as postherpetic neuralgia, be recommended as the first-line treatment medicine by numerous international guidelines.

Particularly, the Pharmacological Mechanism of Prey Bahrain is: α 2-δ site in Prey Bahrain and central nervous system (a complementary subunit of valtage-gated calcium channel) has high affinity.The mechanism of action of Prey Bahrain is still not clear, but the prompting of the result of study of transgenic mice and structurally associated compound (for example gabapentin), and the analgesia in animal model and anticonvulsant action may be relevant with the combination of Prey Bahrain and α 2-δ subunit.In vitro study shows, Prey Bahrain may discharge by regulating the Ca-dependent that the calcium channel function reduce some neurotransmitters.Although Prey Bahrain is the structural derivative of inhibitory neurotransmitter γ-aminobutyric acid (GABA), but its not direct and GABAA, GABAB or benzodiazepine receptors bind, do not increase the neuronic GABAA reaction of vitro culture, do not change GABA concentration in rat brain, GABA is absorbed or degrades without acute effect.But research finds, the neurone of vitro culture is exposed to Prey Bahrain for a long time, and GABA translocator density and functional GABA transport velocity increase.Prey Bahrain does not block the sodium channel, to the opioid receptor non-activity, does not change cyclooxygenase activity, to Dopamine HCL and 5-hydroxytryptamine receptor non-activity, does not suppress the re-uptake of Dopamine HCL, serotonin or norepinephrine.

Le Ruika (Prey Bahrain capsule) went on the market in the U.S. in 2004, be used for postherpetic neuralgia, diabetes peripheral neuralgia, epilepsy, fibromyalgia by drugs approved by FDA, and more than 80 countries and regions listing in the whole world, and having obtained the SFDA approval at Discussion on Chinese Listed, first indication is postherpetic neuralgia.

Prey Bahrain has obtained the adjunctive therapy medicine that European Union's approval is used for the treatment of peripheral nerve characteristic of disease pain and treats as the insane carbuncle outbreak of part in July, 2004.Prey Bahrain has also obtained approval in U.S.A in by the end of December, 2004, be used for diabetes-alleviating peripheral neurophaty related neural characteristic of disease pain and postherpetic neuralgia, first formally gets permission to treat simultaneously the medicine of these two kinds of neuropathic pains so far thereby become the U.S., obtains again the FDA approval and is used for adults with epilepsy partial seizures assisting therapy in 2005.In June, 2007 drugs approved by FDA Lyrica be used for the treatment of fibromyalgia, this is that first of FDA approval is used for the treatment of the medicine of fibromyalgia.

It is a line medication of pain property polyneuropathy, postherpetic neuralgia, central pain that European neurological alliance of association (EFNS) guide in 2006 is recommended Le Ruika.IASP (IASP) Consensus of experts recommended Le Ruika to be treatment postherpetic neuralgia one line medicine in 2007.2007, Le Ruika (Prey Bahrain capsule) was chosen as one of large medical science breakthroughs of year ten by Time.It is unique medicine that has simultaneously maincenter, peripheral nerve pathologic pain indication that Britain NICE guide in 2010 is recommended Le Ruika.The effect characteristics of Le Ruika (Prey Bahrain capsule): the α 2-δ subunit that can suppress the central nervous system voltage-dependent ca channel, reduce flow of calcium ions, reduce the release of the excitatory neurotransmitters such as glutaminate, norepinephrine, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 thereupon, thereby effectively control neurogenic pain, and have anxiety, anticonvulsant effect.

The advantage of Prey Bahrain: quick, lasting, potent alleviation postherpetic neuralgia, significantly improve patients with post herpetic neuralgia somnopathy and pain general impression, serious adverse reaction is rare, do not find that temporarily drug pharmacokinetics interacts, take medicine conveniently, be beneficial to adjustment, absorption is linear dependence with dosage, and is dose dependent.

Prey Bahrain conventional formulation capsule recommended dose is each 75 or 150mg, every day 2 times; Perhaps each 50mg or 100mg, every day 3 times.Initial dose can be each 75mg, every day 2 times; Perhaps each 50mg, every day 3 times.Can increase to each 150mg according to curative effect and tolerance, every day 2 times within 1 week.Bahrain mainly removes through renal excretion due to Prey, and the patient of renal hypofunction should adjust dosage.Above recommended dose is applicable to the patient of CrCl 〉=60 ml/min.Take Prey Bahrain 300mg/ day, 2-4 after week pain do not obtain the patient fully alleviated, as tolerating this product, can increase to each 300mg, every day 2 times, or each 200mg, every day 3 times (600mg/ day).Because untoward reaction is dose-dependently, and untoward reaction can cause higher drug withdrawal rate, and dosage surpasses the rest pain that only is applied to tolerate the 300mg/ per daily dose 300mg/ day and suffers from.

Granted clinical indication comprises in the whole world in Prey Bahrain: the assisting therapy of generalized anxiety disorder, diabetic peripheral neurophaty, postherpetic neuralgia, fibromyalgia syndrome, epilepsy.

The basic demand of medicine is safe, effective, controlled, and it is the basic demand of clinical application that the run-of-the-mill that wherein satisfies medicine requires for example to require medicine stable in its validity period, and the controllability of this drug quality provides guarantee for the security of medicine again.Usually, as a kind of medicine, impurity wherein is necessary to do special stipulation, for example usually requires a certain impurity of regulation lower than 5%, perhaps for example lower than 1%, perhaps for example lower than 0.5%, perhaps for example lower than 0.1%, perhaps for example lower than 0.05%.For same medicine, wherein may contain plurality of impurities, the high-content upper limit of these impurity may be identical also may be different, usually in the Long-term Storage process of medicine for example in the validity period of 2～3 years, foreign matter content wherein should be that metastable, qualified medicine does not allow its foreign matter content in the Long-term Storage process significantly to increase.Prey Bahrain need to control impurity wherein equally, CN102869350A (Ai Jisi for example, CN2011800195930) the background technology part elaboration of specification sheets GABA class medicine easily go out out lactan impurity in molecule, for example wherein explicitly point out, with regard to gabapentin, in molecule, lactan 4-cyclohexyl pyrrolidone is regarded as having more toxicity than gabapentin, and the cyclic lactam of Prey Bahrain is also the by product of not expecting, controls in GABA class medicament research and development and storage and monitoring lactan impurity is important parameter.

Therefore, those skilled in the art expect to have a kind of stay-in-grade Prey Bahrain to be applied to clinical.

Summary of the invention

The purpose of this invention is to provide a kind of have good stability can Prey Bahrain clinical to be applied to.The present invention is achieved in the following ways.

First aspect present invention provides a kind of composition, and it comprises with the following formula I compound:

And as impurity with the Formula Il compound:

According to the composition of first aspect present invention, it is Prey Bahrain bulk drug, and it can be described as " present composition ", " composition of first aspect present invention " etc. in the present invention.In one embodiment, described formula II compound also can be described as " lactan ", " lactan impurity ", " Prey Bahrain lactan ", " Prey Bahrain lactan impurity " etc.

According to the composition of first aspect present invention, its Chinese style I compounds content is greater than 98%, for example usually greater than 99%, for example greater than 99.5%.

Composition according to first aspect present invention, its Chinese style I compounds content is more than 100 times of formula II compounds content, for example said composition Chinese style I compounds content be 100～20000 times of formula II compounds content, for example be 150～15000 times, for example be 200～10000 times, for example be 250～10000 times, for example be 500～10000 times.

As everyone knows, bulk drug as pharmaceutical chemicals, wherein can contain trace impurity more or less, for the present invention, the content of the composition Chinese style I compound that provides is usually greater than 98%, for example usually greater than 99%, for example greater than 99.5%, and for bulk drug, wherein the total content of various impurity is usually less than 2%, for example usually less than 1%, for example less than 0.5%.Above-mentioned phrase " said composition Chinese style I compounds content is 100～20000 times of formula II compounds content " expression, for example in 100g Prey Bahrain bulk drug, if wherein contain 98g formula I compound, the amount of formula II compound is 0.0049～0.98g, and remaining may be other impurity (comprising for example moisture), makes formula I compound amount+formula II compound amount+other total impurities=100g.Specifically, for example the implication of phrase " said composition Chinese style I compounds content is 1000 times of formula II compounds content " expression is, in 100g Prey Bahrain bulk drug, if wherein contain 98g formula I compound, the amount of formula II compound is 0.098g, and other total impurities is 1.902g, like this, content at said composition Chinese style I compound is 98%, and the content of formula II compound is 0.098%.And for the pharmaceutical preparation that comprises pharmaceutical excipient, when mentioning the content as the formula II compound of impurity, refer to that the absolute magnitude of pharmaceutical preparation Chinese style II compound is divided by the percentage ratio of this pharmaceutical preparation Chinese style I compound absolute magnitude, namely, in a pharmaceutical preparation, the content of formula II compound=(weight of this part of weight ÷ pharmaceutical preparation Chinese style I compound of this part pharmaceutical preparation Chinese style II compound) * 100%.

The amount of present composition Chinese style I compound and the amount of formula II compound can be measured by well known to a person skilled in the art method, for example by using reference substance to carry out quantitatively in the HPLC method, for example hereinafter [HPLC method A] is described, and these methods can easily be measured the content of present composition Chinese style I compound and the content of formula II compound.

According to the composition of first aspect present invention, wherein also randomly comprise other impurity.According to the composition of first aspect present invention, wherein also randomly comprise definite RRT1.45 impurity by this paper [HPLC method A].According to the composition of first aspect present invention, wherein also randomly comprise definite RRT1.73 impurity by this paper [HPLC method A].According to the composition of first aspect present invention, wherein also randomly comprise definite RRT1.94 impurity by this paper [HPLC method A].According to the composition of first aspect present invention, wherein also randomly comprise definite RRT2.15 impurity by this paper [HPLC method A].

According to the composition of first aspect present invention, wherein also randomly comprise definite other impurity that is selected from following one or more by this paper [HPLC method A]: RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity.

Composition according to first aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in said composition gained HPLC collection of illustrative plates, described formula I compound peaks area is more than 50 times of formula II compound peaks area, and for example formula I compound peaks area is 100～20000 times or 100～15000 times or 100～10000 times or 100～5000 times of formula II compound peaks area.Perhaps, composition according to first aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and formula II compound is greater than 50, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, for example is 100～5000.

Composition according to first aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT1.45 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.Above-mentioned " peak area ratio of formula I compound and RRT1.45 impurity is greater than 100 " also can be described as " formula I compound peaks area is more than 100 times of RRT1.45 impurity peak area "; Perhaps phrase " peak area ratio of formula I compound and RRT1.45 impurity is 100～20000 " also can be described as " formula I compound peaks area is 100～20000 times of formula II compound peaks area ", under other similar linguistic context of the present invention, identical implication is also arranged.

Composition according to first aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT1.73 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.

Composition according to first aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT1.94 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.

Composition according to first aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT2.15 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.

Composition according to first aspect present invention, the parameters such as the ratio high performance liquid chromatography used between the content of Measurement and Computation present composition Chinese style I compound, formula II compound and other impurity and described formula I compound peaks area and formula II compound (perhaps and other impurity) peak area wherein, can carry out according to [HPLC method A] shown below:

[HPLC method A]

Step 1, two described high performance liquid chromatography of appendix VD of employing Chinese Pharmacopoeia version in 2010 are measured;

step 2, chromatographic condition and system suitability: be weighting agent with octadecylsilane chemically bonded silica, the mixed solution of water-methanol-acetonitrile-phosphate buffered saline buffer volume ratio 550:350:100:1 is moving phase, the detection wavelength is 210nm, number of theoretical plate calculates by Prey Bahrain peak and is not less than 1800, the resolution of Prey Bahrain and lactan impurity peaks should (compound method of wherein said phosphate buffered saline buffer be: get potassium primary phosphate 3.5g and Sodium phosphate dibasic dodecahydrate 14.62g greater than 8, be dissolved in water and be diluted to 1000ml, regulate pH value to 7.0 with phosphoric acid or potassium hydroxide solution, and get final product),

The preparation of step 3, need testing solution: (it can be Prey Bahrain bulk drug to get the sample to be tested that approximately is equivalent to Prey Bahrain 50mg, it can also be the pharmaceutical composition pharmaceutical preparation for example that comprises Prey Bahrain and pharmaceutical excipient, commercially available capsule for example, contain Prey Bahrain in this sample to be tested of taking and be about 50mg), accurately weighed, put in the 50ml measuring bottle, add the moving phase dissolving, stirring or violent jolting 15 minutes, shake up, be diluted to scale with moving phase, shake up, as need testing solution (wherein the concentration of Prey Bahrain is about 1000 μ g/ml);

step 4, reference substance solution (it can be used for measuring the content of the Bahrain of Prey in trial-product) preparation: (this term " reference substance " has those skilled in the art's known implication usually to get Prey Bahrain reference substance, particularly can be used for measuring the content of principal constituent in sample to be tested, it can obtain by commercial sources usually, such as passing through to government organs or the purchases of other commercial undertaking such as National Institute for Food and Drugs Control, also can reach more than 99.9% and obtain by for example being purified to content, in the present invention, if not otherwise indicated, the reference substance of mentioning is all that the content/purity of related material is at the reference substance more than 99.9%) about 50mg, accurately weighed, put in the 50ml measuring bottle, add the moving phase dissolving, stirring or violent jolting 15 minutes, shake up, be diluted to scale with moving phase, shake up, product solution (wherein the concentration of Prey Bahrain is about 1000 μ g/ml) in contrast,

The preparation of step 5,1 ‰ contrast solutions: precision measures above-mentioned need testing solution 5ml, puts in the 250ml measuring bottle, is diluted to scale with moving phase, shakes up; Precision measures this diluent 5ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, as 1 ‰ contrast solutions (this 1 ‰ contrast solution concentration is the thousandth of above need testing solution concentration, and concentration is about 1 μ g/ml);

The preparation of step 6, lactan impurity solution: modus ponens II lactan impurity reference substance is 10mg approximately, and is accurately weighed, puts in the 250ml measuring bottle, adds the moving phase dissolving, is diluted to scale with moving phase, shakes up; Accurate this solution of amount 5ml, put in the 200ml measuring bottle again, is diluted to scale with moving phase, shakes up, as lactan impurity reference substance solution (this lactan impurity reference substance solution is about 1 μ g/ml);

Step 7, assay method:

Step 71, precision measure 1 ‰ contrast solution 50 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of principal constituent chromatographic peak be about 10% of full range;

Step 72, precision measure 1 ‰ contrast solution 50 μ l injection liquid chromatographies, record color atlas to principal constituent (in the present invention, if not otherwise indicated, mention that principal constituent all refers to Prey Bahrain) 8 times of chromatographic peak retention time, this color atlas is designated as color atlas A, reads retention time and the peak area at the principal constituent peak in this color atlas A;

Step 73, precision measure lactan impurity reference substance solution 50 μ l injection liquid chromatographies, record color atlas to 3 times of lactan impurity peaks retention time, this color atlas is designated as color atlas B, reads retention time and the peak area of the lactan impurity peaks in this color atlas B;

Step 74, precision measure the reference substance solution 50 μ l injection liquid chromatographies of step 4 preparation, record color atlas to 3 times of principal constituent chromatographic peak retention time, this color atlas is designated as color atlas C, reads retention time and the peak area at the principal constituent peak in this color atlas C;

step 75, precision measures need testing solution 50 μ l injection liquid chromatographies, record color atlas to 8 times of principal constituent chromatographic peak retention time, this color atlas is designated as color atlas D, in this color atlas D, ignore in solvent peak and optional pharmaceutical excipient peak, take the relative retention time of principal constituent chromatographic peak as 1, read respectively relative retention time in this color atlas D and be about 1.35～1.55 impurity (in the present invention, this impurity is called RRT1.45 impurity), relative retention time is about 1.63～1.83 impurity (in the present invention, this impurity is called RRT1.73 impurity), relative retention time is about 1.84～2.04 impurity (in the present invention, this impurity is called RRT1.94 impurity), relative retention time is about 2.05～2.25 impurity (in the present invention, this impurity is called RRT2.15 impurity) retention time and peak area, and in this color atlas D with color atlas B in the peak area of the corresponding impurity peaks of lactan impurity retention time (it is the lactan impurity peaks),

Step 8, calculating:

In the sample of testing,

the content of formula I compound: the sample weighting amount of dosing in the principal constituent peak-to-peak area in use color atlas C and color atlas D and step 3 and step 4, (be trial-product by external standard method with the calculated by peak area sample to be tested, for example the present composition or by its pharmaceutical preparation for preparing) content of Chinese style I compound, this content can be with % (w/w) expression (in the present invention, the phrase of mentioning " by external standard method with calculated by peak area " is well known to a person skilled in the art, for example Chinese Pharmacopoeia has been put down in writing the content of a large amount of use HPLC methods mensuration material medicines and has been adopted this kind by the method for external standard method with calculated by peak area),

The content of formula II compound: the sample weighting amount of dosing in the peak area of the lactan impurity peaks in use color atlas B and color atlas D and step 3 and step 6, (be trial-product by external standard method with the calculated by peak area sample to be tested, for example the present composition or by its pharmaceutical preparation for preparing) content of Chinese style II compound, this content can represent with % (w/w)

Each long-pending ratio of peak between formula I compound and formula II compound, RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity or other impurity, calculate as pressing formula respectively:

In the present invention, the phraseology that relates to " ratio " or " ratio " is well known to a person skilled in the art.When for example relating to " peak area ratio of formula I compound and RRT1.45 impurity ", if the peak area of formula I compound is 100, the peak area of RRT1.45 impurity is 1, should " peak area ratio of formula I compound and RRT1.45 impurity " can directly be designated as 100, also can be designated as 100:1.

In the present invention, also can calculate the present composition and by the chromatographic purity of its pharmaceutical preparation for preparing, during this chromatographic purity can adopt [HPLC method A] described herein, color atlas D calculates, deduction solvent peak, optional pharmaceutical excipient peak, any peak less than 0.005 times of 1 ‰ contrast solution main peak area wherein ignored, calculate with area normalization method, the principal constituent peak area is the chromatographic purity of this material divided by whole peak area summations.In the present invention, also can calculate the present composition and by the content of total impurities in its pharmaceutical preparation for preparing, it is the summation of the content in composition or medicine system of formula II compound and RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity and other impurity that detects.

Composition according to first aspect present invention, wherein in [HPLC method A], in step 2, octadecylsilane chemically bonded silica used is the chromatographic column of weighting agent, the octadecylsilane chemically bonded silica that can easily obtain from the market various brands is the chromatographic column of weighting agent, its column length can be selected as required, usually can be the column length of 10～30cm, the chromatographic column internal diameter can be 4.6mm usually, flow rate of mobile phase and column temperature also can be adjusted as required, usually flow velocity is 0.8～1.5min, and column temperature is selected the steady temperature between 20～40 ° of C; Especially, in the described chromatographic condition of step 2 of the present invention and system suitability, can suitably select column's length, flow rate of mobile phase, column temperature etc., so that the retention time at Prey Bahrain peak is controlled in the scope of 3～5min, for example be controlled in the scope of 3～4.5min, for example be controlled in the scope of 3～4min.Like this, for example when the retention time at Prey Bahrain peak was 3.5min, color atlas D was recorded to 28min at least in step 64; And being about 1.35～1.55 RRT1.45 impurity for relative retention time, its retention time is generally 4.7～5.4min.Yet, just for the ease of measuring, for example guaranteeing that each chromatographic peak separates the unlikely long recording time that makes color atlas D in satisfactory situation, reasonably complete test in the time in above-mentioned adjustment Prey Bahrain peak to 3～5min scope.In addition, well-known, after above-mentioned such as chromatographic column brand, column length, flow velocity, column temperature etc. appropriately adjusted, common each impurity peaks did not have large variation with respect to the relative retention time at principal constituent peak, and this is the ABC in liquid phase chromatography.

In addition, as well known to those skilled in the art, can directly obtain equally the peak area ratio of formula I compound and each impurity from color atlas D, the peak area of namely using Prey Bahrain peak in chromatographic peak D directly divided by the peak area of the impurity peaks of institute's compute, can obtain described peak area ratio.Yet because the area discrepancy of main peak and impurity peaks is larger, people usually adopt with for example solution of 1%, 0.5% or 0.1% concentration and compare, to reduce measuring error.In the present invention, unless otherwise noted, [HPLC method A] described use 1 ‰ contrast solutions calculate all as mentioned.

the present invention unexpectedly finds, when controlling the RRT1.94 foreign matter content in the present composition within the specific limits, the present invention can be used as the composition of bulk drug and the pharmaceutical preparation for preparing has obviously better stability, particularly work as the peak area ratio of formula I compound and RRT1.94 impurity greater than 100, for example this peak area ratio is 100～20000, be for example 100～15000, be for example 100～10000, be for example 150～10000, it is for example 200～10000 o'clock, lactan in the present composition can be controlled in scope with the initial value no significant difference effectively.

Therefore, according to the composition of first aspect present invention, it comprises with the following formula I compound:

And as impurity with the Formula Il compound:

Its Chinese style I compounds content be more than 100 times of formula II compounds content (for example said composition Chinese style I compounds content be 100～20000 times of formula II compounds content, for example be 150～15000 times, for example be 200～10000 times, for example be 250～10000 times, for example be 500～10000 times)

The peak area ratio of the RRT1.94 impurity that formula I compound and [HPLC method A] are definite is (for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000) greater than 100.

in the present invention, if not otherwise indicated, the RRT1.45 impurity of mentioning, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity is all as defined in this paper [HPLC method A], namely, RRT1.45 impurity refers to use this paper [HPLC method A] mensuration to be about 1.35～1.55 impurity than relative retention time with formula I Compound Phase, RRT1.73 impurity refers to use this paper [HPLC method A] mensuration to be about 1.63～1.83 impurity than relative retention time with formula I Compound Phase, RRT1.94 impurity refers to use this paper [HPLC method A] mensuration to be about 1.84～2.04 impurity than relative retention time with formula I Compound Phase, RRT2.15 impurity refers to use this paper [HPLC method A] mensuration to be about 2.05～2.25 impurity than relative retention time with formula I Compound Phase.

In the present invention, retention time can represent with RT; Relative retention time can represent with RRT, and it is that the retention time of mentioned chromatographic peak is divided by the ratio of the retention time gained at Prey Bahrain peak.

In addition, second aspect present invention also provides a kind of pharmaceutical preparation, wherein comprises the described composition of the arbitrary scheme of first aspect present invention, and the acceptable auxiliary material of pharmacy.

According to the pharmaceutical preparation of second aspect present invention, it is the form that is liquid preparation or solid preparation.

According to the pharmaceutical preparation of second aspect present invention, wherein said liquid preparation is the form of oral liquid or injection liquid.

According to the pharmaceutical preparation of second aspect present invention, wherein said solid preparation is the form of tablet or capsule.

According to the pharmaceutical preparation of second aspect present invention, it is to be quick-release (also often be called and release) or the tablet of slowly-releasing or the form of capsule.

According to the pharmaceutical preparation of second aspect present invention, wherein comprise the formula I compound of 5～500mg in each tablet or capsule.In Prey Bahrain capsule of known listing, comprise that every capsules contains 25,50,75,100,150,200,225 and the specification of 300mg formula I compound, and known Prey Bahrain is to having released clinically its sustained release preparation, its unit formulation content of dispersion will be larger, so in pharmaceutical preparation of the present invention, the amount of activeconstituents formula I compound can change in a big way.

According to the pharmaceutical preparation of second aspect present invention, wherein comprise formula I compound, and as the formula II compound of impurity.

Pharmaceutical preparation according to second aspect present invention, its Chinese style I compounds content is more than 100 times of formula II compounds content, for example this pharmaceutical preparation Chinese style I compounds content be 100～20000 times of formula II compounds content, for example be 150～15000 times, for example be 200～10000 times, for example be 250～10000 times, for example be 500～10000 times.Although added pharmaceutical excipient in pharmaceutical preparation of the present invention, but formula I compound wherein, as RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, the content in pharmaceutical preparation of the present invention of RRT2.15 impurity and proportionlity each other that formula II compound and this paper of impurity has mentioned, can easily measure by [HPLC method A] of the present invention and obtain.

According to the pharmaceutical preparation of second aspect present invention, wherein also randomly comprise definite other impurity that is selected from following one or more by this paper [HPLC method A]: RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity.

Pharmaceutical preparation according to second aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in this pharmaceutical preparation gained HPLC collection of illustrative plates, described formula I compound peaks area is more than 50 times of formula II compound peaks area, and for example formula I compound peaks area is 100～20000 times or 100～15000 times or 100～10000 times or 100～5000 times of formula II compound peaks area.Perhaps, pharmaceutical preparation according to second aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and formula II compound is greater than 50, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, for example is 100～5000.

Pharmaceutical preparation according to second aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT1.45 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.Above-mentioned " peak area ratio of formula I compound and RRT1.45 impurity is greater than 100 " also can be described as " formula I compound peaks area is more than 100 times of RRT1.45 impurity peak area "; Perhaps phrase " peak area ratio of formula I compound and RRT1.45 impurity is 100～20000 " also can be described as " formula I compound peaks area is 100～20000 times of formula II compound peaks area ", under other similar linguistic context of the present invention, identical implication is also arranged.

Pharmaceutical preparation according to second aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT1.73 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.

Pharmaceutical preparation according to second aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT1.94 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.

Pharmaceutical preparation according to second aspect present invention, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition (for example the present invention [HPLC method A]) under, in this pharmaceutical preparation gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT2.15 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.

Pharmaceutical preparation according to second aspect present invention, wherein the parameters such as the ratio high performance liquid chromatography used between the content of Measurement and Computation pharmaceutical preparation Chinese style of the present invention I compound, formula II compound and other impurity and described formula I compound peaks area and formula II compound (perhaps and other impurity) peak area, can carry out according to the present invention [HPLC method A] mentioned above.

According to the pharmaceutical preparation of second aspect present invention, it comprises with the following formula I compound:

And pharmaceutical excipient,

And as impurity with the Formula Il compound:

Its Chinese style I compounds content be more than 100 times of formula II compounds content (for example this pharmaceutical preparation Chinese style I compounds content be 100～20000 times of formula II compounds content, for example be 150～15000 times, for example be 200～10000 times, for example be 250～10000 times, for example be 500～10000 times)

In addition, for pharmaceutical preparation of the present invention, due to its composition that has added the various embodiments of the present invention as activeconstituents, thereby also may exist the formula II compound that can be understood as impurity and other impurity such as including but not limited to following impurity in these pharmaceutical preparations: RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity etc.those skilled in the art know that, these pharmaceutical preparations are in example when [HPLC method A] measures as described in the present invention, can reflect exactly equally composition Chinese style I compound and include but not limited to following impurity: formula II compound, RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity etc., and usually this content measured in joining pharmaceutical preparation than or the bulk drug of peak area ratio and this pharmaceutical preparation of preparation namely for example the content that is measured to of the described composition of the arbitrary embodiment of first aspect present invention than or peak area ratio identical or approaching.

further, third aspect present invention provides the method for preparing the present composition, it comprises the steps: Prey Bahrain is added in the mixing solutions of Virahol and acetonitrile, heating (for example is heated to 40-60 ° of C, for example be heated to 45-55 ° of C, about 50 ° of C for example) make dissolving, add 0.5-5% (v/v) (0.5-2% for example in the mixing solutions, 0.5-1% for example) lactic acid, stir, slowly be cooled to approximately 5 ° of C (can at this temperature standing 2-10 hour) to separate out precipitation, leach precipitation, use washed with isopropyl alcohol, 40 ° of C vacuum-dryings, and get final product.

According to the method for third aspect present invention, wherein said Virahol and acetonitrile volume ratio both is 100:(30～50), preferred volume ratio is 100:(35～45).

In one embodiment, have been found that, to the RRT1.94 impurity that can effectively reduce after the mixing solutions of above-mentioned Virahol and acetonitrile adds appropriate lactic acid in material, and can make the amount of RRT1.94 impurity in material drop to lower by repeating above-mentioned recrystallization process.

Known Prey Bahrain can be used for the assisting therapy for the treatment of or prevention generalized anxiety disorder, diabetic peripheral neurophaty, postherpetic neuralgia (for example postherpetic neuralgia), fibromyalgia syndrome, epilepsy.Therefore, again further, fourth aspect present invention provides composition of the present invention for the preparation of the purposes in the medicine of the assisting therapy for the treatment of or prevention generalized anxiety disorder, diabetic peripheral neurophaty, postherpetic neuralgia (for example postherpetic neuralgia), fibromyalgia syndrome, epilepsy.

Arbitrary embodiment of either side of the present invention can make up with arbitrary embodiment of either side, as long as they contradiction can not occur.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they contradiction can not occur.

In the present invention, when determining the content of the middle Prey Bahrain of various materials (being bulk drug, pharmaceutical preparation etc. such as the present composition) or other impurity, and when determining chromatographic purity in these materials, can adopt the present invention [HPLC method A] mentioned above to carry out.Can easily use in addition [HPLC method A] to measure some preparation performances of pharmaceutical preparation, such as dissolution rate etc.in the present invention, although the inventor not yet knows wherein RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, the chemical structure of RRT2.15 impurity, yet the present invention [HPLC method A] can easily carry out qualitative to these impurity, particularly can determine qualitatively with this parameter of relative retention time by [the HPLC method A] that the present invention stipulates, even in the time of particularly, the chromatogram test condition is done suitable variation, or even in different laboratory measurements, or even measured by different testing crews, or even when using the hplc determination of different brands, this parameter is all relatively-stationary.In addition, for example, the relative retention time of RRT1.94 impurity (calculating take the relative retention time of formula I compound as 1) is 1.84～2.04, this ± 0.2 or ± fluctuation of 0.1 unit is that the pharmaceutical analysis field particularly allows in the efficient liquid phase chromatographic analysis field.

" pharmaceutical excipient " or " pharmaceutically acceptable carrier " that use in pharmaceutical preparation of the present invention (it also can be described as pharmaceutical composition) can be carrier or the auxiliary material of any routine in field of pharmaceutical preparations.The selection of specific support or auxiliary material will be depended on administering mode or disease type and the state that is used for the treatment of particular patient.Be used for the preparation method of suitable drug composition of specific administration pattern fully in pharmaceutical field technician's ken.For example, can be used as thinner, carrier, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and the lubricant etc. that pharmaceutically acceptable carrier comprises the pharmaceutical field routine.In case of necessity, can also add flavouring agent, preservative and sweetener etc. in pharmaceutical composition.

Pharmaceutical composition of the present invention can be made the various ways such as tablet, pulvis, granule, capsule, oral liquid, paste, creme, injectable emulsion (aseptic powder needle for injection).The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.

Existing Prey Bahrain's medicament (for example, capsule etc.) of list marketing, it can be used for treating the assisting therapy of generalized anxiety disorder, diabetic peripheral neurophaty, postherpetic neuralgia, fibromyalgia syndrome, epilepsy.The invention provides a kind of new Prey Bahrain, it has the satisfactory stability performance, so the present invention new Prey Bahrain can be used for treating the assisting therapy of generalized anxiety disorder, diabetic peripheral neurophaty, postherpetic neuralgia, fibromyalgia syndrome, epilepsy equally.

Embodiment

Can conduct further description the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although for to realize that many materials and working method that the object of the invention is used are well known in the art, the present invention still does to describe in detail as far as possible at this.

In test below, use the present invention [HPLC method A], wherein concrete condition determination used is:

chromatographic column: ZORBAX Eclipse XDB-C18 chromatographic column is (available from Agilent company, 200mm*4.6mm*5 μ m), 25 ° of C of column temperature, flow velocity 1ml/min, formula I compound retention time is 3.4min approximately, the resolution of Prey Bahrain and lactan impurity peaks is greater than 10, solvent peak and the auxiliary material peak that adds that the pharmaceutical preparation of pharmaceutical excipient shows all eluted before 2.1min, take the relative retention time of formula I compound as 1, the relative retention time of RRT1.45 impurity is between 1.35～1.55, the relative retention time of RRT1.73 impurity is between 1.63～1.83, the relative retention time of RRT1.94 impurity is between 1.84～2.04, the relative retention time of RRT2.15 impurity is 2.05～2.25.Also find in test, using column length is other brand C18 post of 15～30cm, perhaps column temperature is set in a certain temperature between 20～40 ° of C, perhaps the person is set in a certain value between 0.8～1.5ml/min with flow velocity, and the relative retention time of RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, four impurity of RRT2.15 impurity is all in their above-mentioned respective range.

Raw material preparation example 1: preparation Prey Bahrain raw material

Prepare Prey Bahrain raw material according to the method for embodiment 1 in CN101848905A (Chinese patent application number 200880107269.2) ([0092] section is to [0165] section).

The formula II compound used of product also can use aforesaid method and obtain through the silicagel column purifying in contrast.Use in the present invention the ratio of " content is than (I/II) " expression I compounds content and formula II compounds content, with the peak area ratio of " peak area ratio (I/RRT1.73) " expression color atlas Chinese style I compound and RRT1.45 impurity, the peak area ratio of formula I compound and other impurity is similar expression also.

Measure through [HPLC method A], in this bulk drug, formula I compounds content 98.6%, formula II compounds content 0.76%, content is than (I/II)=130; In bulk drug HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=103, peak area ratio (I/RRT1.73)=96, peak area ratio (I/RRT1.94)=93, peak area ratio (I/RRT2.15)=126.

Raw material preparation example 2: preparation Prey Bahrain raw material

Prepare Prey Bahrain raw material according to the method for embodiment 1 to embodiment 7 ([0096] section is to [0133] section) in CN101821228A (Chinese patent application numbers 200880110859.0, Korea S science and technology institute).

Measure through [HPLC method A], in this bulk drug, formula I compounds content 97.7%, formula II compounds content 1.26%, content is than (I/II)=78; In bulk drug HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=96, peak area ratio (I/RRT1.73)=78, peak area ratio (I/RRT1.94)=81, peak area ratio (I/RRT2.15)=103.

Raw material preparation example 3: preparation Prey Bahrain raw material

Prepare Prey Bahrain raw material according to the method for embodiment 1 to embodiment 9 in CN101585778A (Chinese patent application number 200810037609.0, Shanghai minister nation).

Measure through [HPLC method A], in this bulk drug, formula I compounds content 98.4%, formula II compounds content 0.74%, content is than (I/II)=133; In bulk drug HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=138, peak area ratio (I/RRT1.73)=107, peak area ratio (I/RRT1.94)=74, peak area ratio (I/RRT2.15)=76.

Test compound preparation example 1: formula I compound and the RRT1.94 impurity of preparation substantially pure

with raw material preparation example 3 gained Prey Bahrain as raw material, the chromatographic condition of [HPLC method A], the ZORBAX Eclipse XDB-C18 chromatographic column of use preparation type (available from, Agilent company, 300mm*10mm*7 μ m), the chromatographic peak elutriant of difference interception type I compound and the elutriant of retention time chromatographic peak corresponding to RRT1.94 impurity (), the gained elutriant is desolventized respectively, carry out recrystallization with the method for embodiment 1 hereinafter respectively again, obtain respectively formula I compound and the RRT1.94 impurity of substantially pure, both use [HPLC method A] to measure chromatographic purity all greater than 99.9%, and formula II compound and RRT1.45 impurity do not detected in gained formula I compound, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity.If needed, RRT1.45 impurity, RRT1.73 impurity, RRT2.15 impurity also available similar fashion obtain.

Embodiment 1: prepare Prey of the present invention Bahrain

Prey Bahrain raw material 1g that above raw material preparation example 1 is obtained adds in the mixing solutions of 100ml Virahol and 40ml acetonitrile, being heated to approximately, 50 ° of C make dissolving, add 1.0ml lactic acid in mixing solutions, stir, slowly be cooled to approximately 5 ° of C (at this temperature standing approximately 8 hours) to separate out precipitation, leach precipitation, use washed with isopropyl alcohol, 40 ° of C vacuum-dryings; Repeat again above operation once, obtain can be used as Prey Bahrain of pharmaceutical preparation preparation use, yield 86.4%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I compounds content 99.6%, formula II compounds content 0.03%, content is than (I/II)=3320; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=725, peak area ratio (I/RRT1.73)=453, peak area ratio (I/RRT1.94)=650, peak area ratio (I/RRT2.15)=2854.

Embodiment 2: prepare Prey of the present invention Bahrain

Prey Bahrain raw material 1g that above raw material preparation example 1 is obtained adds in the mixing solutions of 100ml Virahol and 35ml acetonitrile, being heated to approximately, 50 ° of C make dissolving, add 1.35ml lactic acid in mixing solutions, stir, slowly be cooled to approximately 5 ° of C (at this temperature standing approximately 8 hours) to separate out precipitation, leach precipitation, use washed with isopropyl alcohol, 40 ° of C vacuum-dryings, then repeat above operation once, obtain can be used as Prey Bahrain of pharmaceutical preparation preparation use, yield 78.6%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I compounds content 99.7%, formula II compounds content 0.04%, content is than (I/II)=2493; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=520, peak area ratio (I/RRT1.73)=375, peak area ratio (I/RRT1.94)=360, peak area ratio (I/RRT2.15)=1535.

Embodiment 3: prepare Prey of the present invention Bahrain

Prey Bahrain raw material 1g that above raw material preparation example 1 is obtained adds in the mixing solutions of 100ml Virahol and 45ml acetonitrile, being heated to approximately, 50 ° of C make dissolving, add 0.725ml lactic acid in mixing solutions, stir, slowly be cooled to approximately 5 ° of C (at this temperature standing approximately 8 hours) and to separate out precipitation, leach precipitation, use washed with isopropyl alcohol, 40 ° of C vacuum-dryings, and get final product yield 91.3%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I compounds content 99.3%, formula II compounds content 0.198%, content is than (I/II)=502; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=225, peak area ratio (I/RRT1.73)=213, peak area ratio (I/RRT1.94)=210, peak area ratio (I/RRT2.15)=207.

Embodiment 4: prepare Prey of the present invention Bahrain

Prey Bahrain 1g with above embodiment 3 obtains processes (recrystallization repeats 2 times), yield 77.3% according to the method for embodiment 1.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I compounds content 99.8%, formula II compounds content 0.01%, content is than (I/II)=9980; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=8325, peak area ratio (I/RRT1.73)=9720, peak area ratio (I/RRT1.94)=9830, peak area ratio (I/RRT2.15)=8950.

Embodiment 5: prepare Prey of the present invention Bahrain

Prey Bahrain 1g with above embodiment 3 obtains processes (but recrystallization process repeats 3 times), yield 43.5% according to the method for embodiment 1.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I compounds content 99.8%, formula II compounds content 0.005%, content is than (I/II)=19960; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=14430, peak area ratio (I/RRT1.73)=19310, peak area ratio (I/RRT1.94)=13860, peak area ratio (I/RRT2.15)=18550.

Above result shows, although products therefrom impurity reduces greatly, yield can reduce greatly, and this goes out to continue to improve product quality but situation that yield reduces greatly and inadvisable in prerequisite of the bulk drug that obtains to have better quality from industrial production; The described yield of embodiment 4 is being desirable more than 75%, be in gained Prey of the present invention Bahrain bulk drug, formula I compounds content is 500～10000 times of formula II compounds content, and formula I compound is 200～10000th with [HPLC method A] definite RRT1.94 impurity or the peak area ratio of other four impurity, and is desirable.

Embodiment 6: prepare Prey of the present invention Bahrain

Prey Bahrain raw material that above raw material preparation example 2 is obtained is processed according to the method for embodiment 1, obtains can be used as Prey Bahrain of pharmaceutical preparation preparation use, yield 79.6%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I compounds content 99.6%, formula II compounds content 0.013%, content is than (I/II)=7662; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=4225, RRT1.73 impurity does not detect, peak area ratio (I/RRT1.94)=475, peak area ratio (I/RRT2.15)=4854.

Embodiment 7: prepare Prey of the present invention Bahrain

Prey Bahrain raw material that above raw material preparation example 3 is obtained is processed according to the method for embodiment 1, obtains can be used as Prey Bahrain of pharmaceutical preparation preparation use, yield 81.3%.

Measure through [HPLC method A], in the present embodiment gained Prey Bahrain, formula I compounds content 99.5%, formula II compounds content 0.083%, content is than (I/II)=1199; In the present embodiment gained Prey Bahrain HPLC collection of illustrative plates, peak area ratio (I/RRT1.45)=645, peak area ratio (I/RRT1.73)=312, peak area ratio (I/RRT1.94)=275, peak area ratio (I/RRT2.15)=1635.

The inventor also finds in other test, if in above embodiment 1-7, do not add lactic acid, can not effectively improve peak area ratio (I/RRT1.94), particularly be difficult to this peak area ratio (I/RRT1.94) is brought up to more than 150, namely can not effectively remove RRT1.94 impurity wherein.For example in embodiment 1, if do not add lactic acid, peak area ratio in products therefrom (I/RRT1.94) is 133, and in embodiment 2, if do not add lactic acid, peak area ratio in products therefrom (I/RRT1.94) is 117.

Embodiment 8: contain the preparation of the artificial combination thing of Prey Bahrain and RRT1.94

Use and above " test with compound preparation example 1 " formula I compound and the RRT1.94 impurity for preparing, will both make up according to a certain percentage (formula I compound and RRT1.94 impurity weight ratio reach following table institute train value to meet both peak area ratio in the wide region of 100:0.0001～0.5, when for example both weight ratio is the 100:0.01 combination, the peak area ratio of demonstration approximately 360; Because both weight differential is large, proportioning makes when mixing and both is dissolved in methyl alcohol, then remove methyl alcohol in order to both mix), obtain many parts of compositions, these proportioning combination resulting compositions are measured the peak area ratio (I/RRT1.94) that shows respectively following table, i.e. numerical value shown in following table I/RRT1.94 hurdle under [HPLC method A] condition.

Composition No	#80	#81	#82	#83	#84	#85	#86	#87	#88	#89	#891
												I/RRT1.94	35710	7143	3570	715	310	210	143	70	36	24	18
II increment/%	0	0	0	0.0006	0.0011	0.0018	0.072	0.168	0.413	1.244	2.429

50C-4M test: each powder composition of above #80 to #891 is placed in sealed glass jars, is placing April (can represent with " 50C-4M " in the present invention to place under these 50 ° of C and dispose April) under 50 ° of C.Then measure the content (% of this sample Chinese style II compound, represent with C4), content (the % of its Chinese style II compound when also measuring this sample without 50C-4M in addition, represent with C0), calculate in this sample the content increased value of formula II compound after 50C-4M, be II increment (%), calculate with following formula: II increment=C4-C0.Result sees the above table, as seen, atomic greater than 200 up-to-date style II compound increasing amounts at peak area ratio (I/RRT1.94), and when peak area ratio (I/RRT1.94) less than 200 the time, display type II compound increases obviously, particularly itself reach more than 1% without Prey Bahrain Chinese style II compounds content of the substantially pure of formula II compound when reaching 24 when peak area ratio (I/RRT1.94), fully can not fulfilling medicinal requirements.Usually in the Prey Bahrain as the medicinal raw material medicine, the content of formula II compound should be lower than 0.2%, and the content of Prey Bahrain bulk drug Chinese style II compound of fine quality should lower than 0.1%, particularly preferably be lower than 0.05%; And if be unacceptable higher than 0.5%.Above-mentioned 50C-4M test method can be used for the context of the invention.

Need to prove, when calculating comprises the pharmaceutical preparation of pharmaceutical excipient, owing to wherein being added with pharmaceutical excipient, so the content of formula I compound in pharmaceutical preparation can represent with the absolute magnitude of the preparation Chinese style I compound percentage ratio divided by the theoretical labelled amount gained of this part preparation Chinese style I compound; And for wherein formula II compound, its content is to represent with the absolute magnitude of the said preparation Chinese style II compound percentage ratio divided by the absolute magnitude of formula I compound, when if other material as impurity represents with content in pharmaceutical preparation, also have and implication like formula II compounds.

Embodiment 81: the pharmaceutical preparation that contains Prey Bahrain and RRT1.94

With each powder composition of above #80 to #891 as bulk drug, get respectively its 75mg, evenly also cross 80 mesh sieves with lactose 10mg, W-Gum 13mg, talcum powder 2mg by ground and mixed respectively, pack in empty hard capsule, obtain containing 11 kinds of capsules of formula I compound, every capsules contains Prey Bahrain 75mg, makes 5000 for every batch.Use these capsules of 50C-4M test determination formula II compound amount increased value after 50C-4M processes.Result shows, the result of " II increment " bulk drug corresponding with it of each capsule is basic identical, for example the II increment of each powder composition gained capsule of #80 to #82 is 0, the II increment of each powder composition gained capsule of #83 to #85 is all in 0.0005～0.002% scope, in the II increment of each powder composition gained capsule of #86 to #891 and upper table, the II increment of corresponding bulk drug differs less than 0.05% unit, and for example the II increment with #89 raw material gained capsule is 1.265%.

Embodiment 9: contain the preparation of the artificial combination thing of Prey Bahrain and RRT1.94

the formula I compound that appropriate above " test with compound preparation example 1 " prepared or RRT1.94 impurity add to above in embodiment 1 gained Prey of the present invention Bahrain (then removing methyl alcohol so that the mode of mixing of materials is added jointly to be dissolved in methyl alcohol), so that containing the artificial combination thing of Prey Bahrain and RRT1.94 and other impurity, gained measures the peak area ratio (I/RRT1.94) that shows respectively following table under [HPLC method A] condition, can reduce peak area ratio (I/RRT1.94) during for example to embodiment 1 gained Prey Bahrain interpolation RRT1.94 impurity.

Composition No	#90	#91	#92	#93	#94	#95	#96	#97	#98	#99	#991
												I/RRT1.94	32300	9550	3520	690	325	205	165	81	35	25	20
II increment/%	0	0	0	0.0005	0.0011	0.0015	0.077	0.165	0.431	1.289	2.503

According to the II increment (%) of each artificial composition more than the 50C-4M determination of test method after 50C-4M disposes.Result and embodiment are substantially similar.As seen, in as Prey Bahrain of bulk drug when control peak area ratio (I/RRT1.94) greater than 150 particularly greater than 200 the time, be very favorable for the control of the amount of its Chinese style II lactan impurity compound.

Embodiment 91: the pharmaceutical preparation that contains Prey Bahrain and RRT1.94

With each powder composition of above #90 to #991 as bulk drug, get respectively its 75mg, evenly also cross 80 mesh sieves with lactose 10mg, W-Gum 13mg, talcum powder 2mg by ground and mixed respectively, pack in empty hard capsule, obtain containing 11 kinds of capsules of formula I compound, every capsules contains Prey Bahrain 75mg, makes 5000 for every batch.Use these capsules of 50C-4M test determination formula II compound amount increased value after 50C-4M processes.Result shows, the result of " II increment " bulk drug corresponding with it of each capsule is basic identical, for example the II increment of each powder composition gained capsule of #90 to #92 is 0, the II increment of each powder composition gained capsule of #93 to #95 is all in 0.0005～0.0018% scope, in the II increment of each powder composition gained capsule of #86 to #891 and upper table, the II increment of corresponding bulk drug differs less than 0.05% unit, and for example the II increment with #89 raw material gained capsule is 1.273%.

As seen above embodiment 81 and embodiment 91 results have in the pharmaceutical preparation of raw material preparation of RRT1.94 impurity of certain content, and the degraded product formula II lactan impurity of activeconstituents has and the essentially identical Changing Pattern of bulk drug equally.Therefore for the pharmaceutical preparation of the composition of first aspect present invention and second aspect, the RRT1.94 impurity that wherein contains lower aq, and it is in the HPLC collection of illustrative plates that [HPLC method A] measures, peak area ratio (I/RRT1.94) is preferred greater than 150, and particularly peak area ratio (I/RRT1.94) is very preferred greater than 200.

Pharmaceutical preparation example 1: the capsule medicine composition for preparing Prey Bahrain

Get embodiment 1 gained Prey Bahrain 75mg and lactose 10mg, W-Gum 13mg, talcum powder 2mg by even 80 mesh sieves of also crossing of ground and mixed, pack in empty hard capsule, obtain Prey Bahrain capsule, every capsules contains Prey Bahrain 75mg, 5000 of the every batch of systems.Be called in the present invention capsule 1 take embodiment 1 gained Prey Bahrain as the capsule that raw material obtains thus.

Equally, respectively with embodiment 2,3,4,5,6,7 gained Prey Bahrain as raw material, prepare capsule with the method for capsule 1, obtain respectively capsule 2, capsule 3, capsule 4, capsule 5, capsule 6, capsule 7.

Equally, respectively with raw material preparation example 1, raw material preparation example 2, raw material preparation example 3 gained Prey Bahrain as raw material, prepare capsule with the method for capsule 1, obtain respectively capsule 01, capsule 02, capsule 03.

Pharmaceutical preparation example 2: the tablet medicine composition for preparing Prey Bahrain

Prepare 10000 scales, every consists of: embodiment 2 gained Prey Bahrain 75mg, N.F,USP MANNITOL 100mg, W-Gum 90mg, colloid silica 2mg, polyvidone (K25) 5mg, Magnesium Stearate 3mg.

The preparation method: (a) each material was crushed to 60～80 orders in advance.Prey Bahrain, N.F,USP MANNITOL, W-Gum (2/3 amount) are loaded in fluidised bed granulator; (b) polyvidone is dissolved in the water to form solution, and with on the particle of this spray solution in this fluidised bed granulator, with these mixture granulations to form particulate mixtures; (c) this particulate mixtures is dried to approximately 1.0% to about 2.5% end point moisture content; (d) this particulate mixtures with step (c) mixes with colloid silica, surplus W-Gum and Magnesium Stearate, and blending is to form final blend; (e) use tabletting machine to be pressed into tablet by final blend.

Pharmaceutical preparation example 3: the slow releasing tablet pharmaceutical composition for preparing Prey Bahrain

Prepare 10000 scales, every consists of: embodiment 3 gained Prey Bahrain 150mg, hypromellose 2208 (Methocel K15M) 150mg, W-Gum 100mg, Carbopol 941 (

, 71G) 10mg, colloid silica 5mg, Magnesium Stearate 3mg.

The preparation method: (1) was ground into 60-80 purpose fine powder in advance with each component.In mixing tank, activeconstituents and small part (approximately 15%) hypromellose is pre-mixed; (2) follow in mixing tank, mixture and remaining hypromellose, W-Gum, carbomer in step (1) are mixed, then add colloid silica and Magnesium Stearate, material is fully mixed; (3) by with final mixture compressing tablet in suitable tabletting machine, prepare the matrix tablet of slow release type.

Pharmaceutical preparation example 4: the oral medicine liquid composition for preparing Prey Bahrain

Preparation 10000ml scale, every 5ml oral liquid consists of: embodiment 3 gained Prey Bahrain 75mg, propylene glycol 0.5ml, mud moor gold ethyl ester 10mg, stevioside 5mg, water add to 5ml in right amount.

Preparation method: with suitable quantity of water, each component is mixed, dissolved, add water to full dose, divide to install in vial, namely get the pharmaceutical preparation of drink form.

Stability test example 1: various samples are carried out study on the stability

Investigate sample: raw material preparation example 1,2,3 gained Prey Bahrain raw materials, Prey Bahrain of embodiment 1,2,3,4,5,6,7 preparations, the capsule 1 of pharmaceutical preparation example 1 preparation is to capsule 7 and capsule 01 to capsule 03, the tablet of pharmaceutical preparation example 2 preparations, the slow releasing tablet of pharmaceutical preparation example 3 preparations, pharmaceutical preparation example 4 oral liquids, and commercially available capsule (Prey Bahrain capsule, the 75mg/ grain, the accurate word J20100102 of traditional Chinese medicines, lot identification mark 9408423023, in January, 2012 production time) totally 24 samples as sample, carry out study on the stability.

Above-mentioned each bulk drug or capsule or tablet are packed with aluminium foil bag respectively, oral liquid is packaged in vial, be placed in 45 ° of C thermostat containers and place May (can be described as " 45C-5M test "), measure the content of each sample activeconstituents when 0 month (before being setting-out) and May and the content of formula II compound.

For each sample, with May active component content divided by the percentage value of 0 month active component content gained, the activeconstituents relative content (%) as high-temperature treatment after May, namely calculating formula is as follows:

Activeconstituents relative content (%)=(0 month content of content ÷ in May) * 100%

For each sample, measure the content (% of this sample Chinese style II compound, represent with C5), content (the % of its Chinese style II compound when also measuring this sample without 45C-5M in addition, represent with C0), calculate in this sample the content increased value of formula II compound after 45C-5M, namely II increment (%), calculate with following formula: II increment=C5-C0.

After above 45C-5M test was disposed, the activeconstituents relative content of commercially available capsule was 97.7%, and the content increased value of formula II compound is 0.076% after 45C-5M; Other each sample the results are shown in following table:

Sample	I content	The II increment	Sample	I content	The II increment
						Raw material preparation example 1	94.4%	0.163%	Capsule 01	87.5%	0.274%
Raw material preparation example 2	92.7%	0.194%	Capsule 02	85.8%	0.304%
						Raw material preparation example 3	93.1%	0.206%	Capsule 03	86.4%	0.338%
Embodiment 1	98.7%	<0.001%	Capsule 1	96.4%	<0.001%
						Embodiment 2	98.8%	<0.001%	Capsule 2	97.3%	<0.001%
Embodiment 3	99.2%	0.0014%	Capsule 3	96.2%	0.0018%
						Embodiment 4	98.4%	0	Capsule 4	96.7%	0
Embodiment 5	98.6%	0	Capsule 5	98.1%	0
						Embodiment 6	98.7%	<0.001%	Capsule 6	96.5%	<0.001%
Embodiment 7	98.9%	0.0011%	Capsule 7	96.8%	0.0014%
						Pharmaceutical preparation example 2	96.5%	0.0012%	?	?	?
Pharmaceutical preparation example 3	96.8%	0.0021%	?	?	?
						Pharmaceutical preparation example 4	96.3%	0.0024%	?	?	?

In table, " I content " hurdle represents the relative content of activeconstituents formula I compound.

From table result as seen, Prey of the present invention Bahrain all have under bulk drug or preparation state than in the better chemical stability of result of prior art preparation, show that particularly one of them expects that quite the lactan impurity of avoiding is in controlled level.

Claims

1. composition, it comprises with the following formula I compound:

And as impurity with the Formula Il compound:

2. according to claim 1 composition, its Chinese style I compounds content is more than 100 times of formula II compounds content, for example said composition Chinese style I compounds content be 100～20000 times of formula II compounds content, for example be 150～15000 times, for example be 200～10000 times, for example be 250～10000 times, for example be 500～10000 times.

3. the composition of according to claim 1 to 2, wherein also randomly comprising can be by [HPLC method A] definite RRT1.94 impurity; Further, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition under, in said composition gained HPLC collection of illustrative plates, the peak area ratio of described formula I compound and RRT1.94 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.

4. the composition of according to claim 1 to 3, wherein also randomly comprising can be by [HPLC method A] definite other impurity that is selected from following one or more: RRT1.45 impurity, RRT1.73 impurity, RRT1.94 impurity, RRT2.15 impurity; Further, its can make resolution between formula I compound and formula II compound greater than 8 high performance liquid chromatography chromatographic condition under, in said composition gained HPLC collection of illustrative plates:

The peak area ratio of described formula I compound and RRT1.45 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.；

The peak area ratio of described formula I compound and RRT1.73 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000;

The peak area ratio of described formula I compound and RRT1.94 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000; And/or

The peak area ratio of described formula I compound and RRT2.15 impurity is greater than 100, and for example this peak area ratio is 100～20000, is for example 100～15000, is for example 100～10000, is for example 150～10000, for example is 200～10000.

5. the composition of according to claim 1 to 4, the method for wherein said [HPLC method A] comprises the following steps:

Step 3, need testing solution preparation: get the sample to be tested that approximately is equivalent to Prey Bahrain 50mg, accurately weighed, put in the 50ml measuring bottle, add the moving phase dissolving, stirring or violent jolting 15 minutes shake up, and are diluted to scale with moving phase, shake up, as need testing solution;

The preparation of step 4, reference substance solution: get approximately 50mg of Prey Bahrain reference substance, accurately weighed, put in the 50ml measuring bottle, add the moving phase dissolving, stir or violent jolting 15 minutes, shake up, be diluted to scale with moving phase, shake up, in contrast product solution;

The preparation of step 5,1 ‰ contrast solutions: precision measures above-mentioned need testing solution 5ml, puts in the 250ml measuring bottle, is diluted to scale with moving phase, shakes up; Precision measures this diluent 5ml, puts in the 100ml measuring bottle, is diluted to scale with moving phase, shakes up, as 1 ‰ contrast solutions;

The preparation of step 6, lactan impurity solution: modus ponens II lactan impurity reference substance is 10mg approximately, and is accurately weighed, puts in the 250ml measuring bottle, adds the moving phase dissolving, is diluted to scale with moving phase, shakes up; Accurate this solution of amount 5ml, put in the 200ml measuring bottle again, is diluted to scale with moving phase, shakes up, as lactan impurity reference substance solution;

Step 7, assay method:

Step 72, precision measure 1 ‰ contrast solution 50 μ l injection liquid chromatographies, record color atlas to 8 times of principal constituent chromatographic peak retention time, and this color atlas is designated as color atlas A, read retention time and the peak area at the principal constituent peak in this color atlas A;

Step 8, calculating:

In the sample of testing,

The content of formula I compound: the sample weighting amount of dosing in the principal constituent peak-to-peak area in use color atlas C and color atlas D and step 3 and step 4, by the content of external standard method with calculated by peak area sample to be tested Chinese style I compound,

The content of formula II compound: the sample weighting amount of dosing in the peak area of the lactan impurity peaks in use color atlas B and color atlas D and step 3 and step 6, by the content of external standard method with calculated by peak area sample to be tested Chinese style II compound,

6. the composition of according to claim 1 to 5, it comprises with the following formula I compound:

And as impurity with the Formula Il compound:

7. a pharmaceutical preparation, wherein comprise the described composition of claim 1-6 any one, and the acceptable auxiliary material of pharmacy.

8. as described according to claim 7 pharmaceutical preparation, its feature embodiment as arbitrary in the specification sheets second aspect.

9. the method for preparing claim 1-6 any one composition, it comprises the steps: Prey Bahrain is added in the mixing solutions of Virahol and acetonitrile, heating makes dissolving, add the lactic acid of 0.5-5% (v/v) in the mixing solutions, stir, slowly be cooled to approximately 5 ° of C to separate out precipitation, leach precipitation, use washed with isopropyl alcohol, 40 ° of C vacuum-dryings, and get final product.

10. claim 1-6 any one composition or claim 7-8 any one pharmaceutical preparation are for the preparation for the treatment of or prevention generalized anxiety disorder, diabetic peripheral neurophaty, the postherpetic neuralgia purposes in the medicine of the assisting therapy of postherpetic neuralgia, fibromyalgia syndrome, epilepsy for example.