CN101111251A - Novel formulation of pyridoxal 5'-phosphate and method of preparation - Google Patents

Abstract

A pyridoxal-5'-phosphate pharmaceutical formulation suitable for oral administration is provided comprising a dissolution profile, when measured in a standard dissolution apparatus, according to the United States Pharmacopoeia dissolution test, at 37 DEG C. in a 0.05M phosphate buffered solution having a pH of 6.8 at 75 rpm, as follows: (a) greater than about 30% at 15 minutes, (b) greater than about 85% at 30 minutes, (c), greater than about 90% at 45 minutes, or (d) greater than about 95% at 60 minutes. Additionally, in vivo oral intake of between 15 and 60 mg/kg of a pyridoxal-5'-phosphate pharmaceutical formulation can produce a maximum plasma level (Cmax) of between about 1 mg/L and 8 mg/L. A pharmaceutical formulation provided comprises (a) a core, wherein said core comprises pyridoxal-5'-phosphate or a pharmaceutically acceptable salt thereof; (b) a sub-coat surrounding the core; and (c) an enteric coat surrounding the sub-coat.

Description

5'-pyridoxal 5-phosphate new formulation and preparation method thereof

Technical field

The present invention relates to 5 '-pharmaceutical preparation of pyridoxal 5-phosphate and preparation method thereof.

Background technology

5 '-pyridoxal 5-phosphate can be used for multiple diseases, such as hypertension, cerebrovascular disease, cardiovascular disease and treatment of diabetes and prevention.Referring to for example the 6th, 051,587,6,417,204,6,548,519,6,586,414,6,605,612,6,667,315,6,780,997,6,677,356,6,489,348 and 6,043, No. 259 United States Patent (USP)s.5 '-pyridoxal 5-phosphate has the commercial preparation of multiple dosage.But present available supplement (supplement) discharge usually than 5 of low dosage '-pyridoxal 5-phosphate, too low for this dosage of hypertension, cerebrovascular disease, cardiovascular disease and treatment of diabetes.Therefore, in order to obtain appropriate therapeutic, need every day usually and repeatedly take described supplement.

The invention provides novel combination of oral medication, compare with the prior art preparation, described compositions can discharge that quantity increases 5 '-pyridoxal 5-phosphate.The present invention also provides the novel medicament compositions, overcome with take in high dose 5 '-gastrointestinal side effect that pyridoxal 5-phosphate is relevant.

Summary of the invention

In one embodiment, be applicable to 5 of oral administration '-pyridoxal 5-phosphate pharmaceutical preparation, when according to the American Pharmacopeia dissolution test, in the standard dissolving device, in the 0.05 M phosphate buffer of pH 6.8, when under 37 ℃ and 75rpm, measuring, it comprises following dissolution characteristic: (a) surpassed about 30% in the time of 15 minutes, (b) surpassed approximately 85% in the time of 30 minutes, (c) surpassed approximately 90% in the time of 45 minutes, perhaps (d) surpassed about 95% in the time of 60 minutes.In the body 5 of oral absorption 15～60 mg/kg therefore, '-during pyridoxal 5-phosphate pharmaceutical preparation embodiment, can produce the maximum blood plasma level (C of about 1mg/L～8 mg/L _Max).

In one embodiment, described pharmaceutical preparation comprises (a) label, and wherein said label comprises 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica; (b) sub-coat (sub-coat) of parcel label; And the enteric coating that (c) wraps up described sub-coat.Described embodiment can be any suitable peroral dosage form such as tablet or capsule.

In one embodiment, described preparation comprises 5 of at least 50 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica.

Embodiment comprise preparation 5 '-method of pyridoxal 5-phosphate pharmaceutical preparation embodiment, wherein said preparation comprises the premix of 5 of at least 50 weight % '-pyridoxal 5-phosphate.

Embodiment comprise administration can increase 5 of patient's compliance '-method of pyridoxal 5-phosphate pharmaceutical preparation embodiment.

Description of drawings

Fig. 1 is a flow chart, and its demonstration is used for the preparation process of the granular preparation of enteric coated tablet production.

Fig. 2 is a flow chart, and its demonstration is used for the preparation process of semi-finished product (semi-final) mixture preparation and the final press sheet formulation and the tablet label of enteric coated tablet production.

Fig. 3 is a flow chart, and it shows tablet label coating so that the step of enteric coated tablet to be provided.

Fig. 4 is a line diagram, and it shows the comparison of enteric coated tablet dissolution characteristic and the stripping of tablet label.

Fig. 5 is a line diagram, and it shows the comparison of enteric coated tablet dissolution characteristic and the stripping of tablet label.

Fig. 6 is a line diagram, and it shows the comparison of enteric coated tablet dissolution characteristic and the stripping of tablet label.

Fig. 7 is a line diagram, and it shows the comparison of enteric coated tablet dissolution characteristic and the stripping of tablet label.

Fig. 8 has shown the low, high of enteric coated tablet and has on average discharged percentages.

The specific embodiment

Definition

Term " percentage by weight (weight %) " means specific compound or the excipient percentage by weight with respect to the gross weight of the compositions of being made up of described chemical compound or excipient.

Term " percent weight in volume (%w/v) " means specific compound or the excipient percentage by weight with respect to the cumulative volume of the solution of being made up of described chemical compound or excipient.

Term " granule " means the state of material, it is characterized in that existing with discontinuous granule, bead, globule or microgranule, and is irrelevant with their size, shape or form.

Term " particle complex (multiparticulate) " is when here using, and the meaning means a plurality of discontinuous, and perhaps accumulative granule, bead, globule, microgranule or their mixture are irrelevant with their shape, size or form.

Term " disintegrating agent " is when here using, and the meaning means anyly to be used to impel solid block to split into particulate material littler, that be easier to disperse or dissolve in solid dosage forms.

Term " binding agent " is when here using, and the meaning means that any helping maintains together material with tablet." binding agent " comprises any in tablet system granule process, is used to cause the adherent material of powder particle.

Term " lubricant " is when here using, and the meaning means any use to reduce the material of frictional force in the tablet tabletting process in tablet formulation.Term " lubricant " also comprises the material that all tablets that allow compacting withdraw from fully from tablet machine.

Term " fluidizer " is when here using, and the meaning means any use reducing the material of frictional force in the tabletting process in tablet formulation, perhaps anyly is used for impelling powder at the mobile material of tabletting process.

Term " antitack agent " is when here using, and the meaning means and prevents that in process of production tablet formulation composition and tablet machine from dashing, any material of mould adhesion.

Term " excipient " is when here using, and the meaning means mixes any inert substance of producing pharmaceutical dosage form with active medicine.

Term " coloring agent " is when here using, and the meaning means any material that is used to give pharmaceutical preparation (for example tablet) color.

Term " sub-coat ", " sealing coat (seal coat or sealing coat) " when using, mean any protectiveness coating here, comprise moistureproof or solvent-proof coating.

Term " enteric coating " or " enteric coating " be when here using, and the meaning means any coating or the shell that is wrapped on the tablet, their not disintegrates under one's belt, but disintegrate and medicine or active component be discharged into enteral in intestinal.

Use the compliance that helps to increase the patient as pharmaceutical composition of the present invention.As everyone knows, patient's compliance and medicine are taken between the frequency and are existed negative correlation.It is high more that prescription drug is taken in frequency, and patient's compliance ratio is low more.Be well known that equally when prescription drug is difficult to administration and drug administration with uncomfortable when relevant, patient's compliance descends.Since compositions by the peroral dosage form of every day 1 or 2 times provide 5 of high dose '-pyridoxal 5-phosphate, and described peroral dosage form size is easy to swallow, so pharmaceutical composition according to the present invention has improved patient's compliance.

To 5 of high dose '-restrictive factor of pyridoxal 5-phosphate tolerance is a gastrointestinal upset, its feature is mainly nausea and vomiting.The invention provides the novel medicament compositions, its be applicable to high dose 5 '-oral administration of pyridoxal 5-phosphate, and have very little gastrointestinal side effect.In addition, come control drug release, help in the period that prolongs, to keep medicine in the intravital treatment concentration of machine by the rate of release of controlling described preparation.

Pharmaceutical composition provided by the invention can discharge 5 of high dose '-pyridoxal 5-phosphate.Present available prior art preparation each dosage form release usually reaches 5 of 50mg '-pyridoxal 5-phosphate.Correspondingly, desirable 5 in order to realize '-the pyridoxal 5-phosphate treatment level, prior art preparation every day must administration 2～3 times or more times.On the contrary, pharmaceutical composition of the present invention contain a high proportion of 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica.

The single dosage form of described pharmaceutical composition can comprise 5 of 250～1000mg '-pyridoxal 5-phosphate.Pharmaceutical composition according to the present invention is applicable to administration every day 1 time or 2 times.

A high proportion of 5 '-pyridoxal 5-phosphate or its salt makes it possible to provide described pharmaceutical composition with the dosage form littler than prior art preparation formulation.Therefore, pharmaceutical composition according to the present invention is easy to administration, is specially adapted to those be difficult to swallow bolus or capsular patients.

Preparation

The present invention comprise be applicable to 5 of oral administration '-pyridoxal 5-phosphate pharmaceutical preparation, when in the standard dissolving device, according to the American Pharmacopeia dissolution test, when under 37 ℃, the 0.05M phosphate buffer of pH6.8 and 75rpm, measuring, it comprises following stripping feature: (a) surpassed about 30% in the time of 15 minutes, (b) surpassed approximately 85% in the time of 30 minutes, (c) surpassed approximately 90% in the time of 45 minutes, perhaps (d) surpassed about 95% in the time of 60 minutes.In addition, in the body 5 of oral absorption 15～60mg/kg '-pyridoxal 5-phosphate pharmaceutical preparation embodiment can produce the maximum blood plasma level (C of about 1mg/L～8mg/L _Max).The structural intergrity of the embodiment of the coating of pharmaceutical composition of the present invention is subjected in the stomach influence of acid condition very little.Therefore, according to the American Pharmacopeia dissolution test, in 0.1N HCl, under 37 ℃ and 75rpm, the embodiment of described pharmaceutical composition can have that stripping is less than or equal to 10% dissolution characteristic in the time of 120 minutes.

Pharmaceutical composition according to the present invention provide 5 of improvement '-the pyridoxal 5-phosphate bioavailability.The compositions of oral absorption 15～60mg/kg can produce the maximum blood plasma level (C of 5 of about 1～about 8mg/L '-pyridoxal 5-phosphate in the body _Max).Preferably, in the body compositions of oral absorption 15～60mg/kg in the average plasma levels that produced about 0.1～about 2mg/L after the administration in 2 hours to the administration during 24 hours.

In one embodiment, described pharmaceutical composition comprises 5 of about 66.3 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica, the microcrystalline Cellulose of about 21.6 weight %, about 4.0% cross-linking sodium carboxymethyl cellulose, the polyvidone of about 4.7 weight %, about 2.0% Pulvis Talci, the colloidal silica of about 0.5 weight %, and the magnesium stearate of about 1.0 weight %.

Can use 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica prepares pharmaceutical composition of the present invention.5 of one water and anhydrous form '-pyridoxal 5-phosphate all is applicable to preparation of drug combination of the present invention.5 '-pyridoxal 5-phosphate can provide with the form with the compatible salt that counter ion was become of materia medica, such as but not limited to citrate, tartrate, disulfate etc.The compatible salt of described materia medica can form with multiple acid, and described acid includes but not limited to hydrochloric acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid etc.Compare with corresponding free alkaline form, described salt form be more prone to be dissolved in aqueous or other proton solvents in.

Preferably, pharmaceutical composition comprises the microcrystalline Cellulose of the about 0.100mm of particle diameter, such as but not limited to Avicel PH102.Polyvidone preferably has 27～33 K value.In a preferred embodiment, polyvidone is PVP K30.

Other drug be can further comprise according to pharmaceutical composition of the present invention and acceptable carrier, dispersant and excipient learned.Appropriate excipients comprises filler such as sugar, comprise lactose, sucrose, mannitol or sorbitol, perhaps cellulosics such as corn starch, wheaten starch, rice starch, potato starch, gelatin, Tragacanth, methylcellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone.Disintegrating agent can comprise crospolyvinylpyrrolidone, agar, alginic acid or their salt such as sodium alginate.Pharmaceutical composition can also comprise suitable solid or gel phase carrier or excipient.The example of this carrier or excipient includes but not limited to: calcium carbonate, calcium phosphate, various sugar, starch, cellulose derivative, gelatin, and polymer such as Polyethylene Glycol.Other excipient can comprise antitack agent such as Pulvis Talci, colloidal silica, titanium dioxide, calcite, microcrystalline Cellulose, Metallic stearates and barium sulfate.Described compositions can also comprise the system particle binders, such as but not limited to alginic acid.

In one embodiment of the invention, pharmaceutical composition comprises: (a) label, wherein said label comprise 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica; (b) sub-coat of parcel label; And the enteric coating that (c) wraps up sub-coat.Randomly, described pharmaceutical composition further comprises the ornamental colored coating that wraps up enteric coating.

In another embodiment of the invention, label comprises 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyvidone, Pulvis Talci, colloidal silica and magnesium stearate.

Sub-coat (or sealing coat) and enteric coating guarantee to comprise 5 '-label of pyridoxal 5-phosphate can pass through stomach intactly, then optionally in intestinal absorption.Enteric coating is that pH is dependent, compares with the sour environment of stomach, preferably presents unstability in the alkaline relatively environment of intestinal.Sub-coat or sealing coat provide extra protection for label, minimize to guarantee label disintegrate under one's belt.Sealing coat and enteric coating are well known to those skilled in the art.As long as preferably with 5 '-stripping of pyridoxal 5-phosphate label is limited in the intestinal, and any suitable sealing coat and the combination of enteric coating all can be used for as preparation of drug combination of the present invention.

Sub-coat or sealing coat protection ingredient in tablets are avoided the influence of water in the aqueous enteric coating dispersion, to guarantee the stability of dosage form.Sub-coat comprises resin, as Lac, zein etc., and is applied in the dosage form by known method.The sub-coat that is used for the sugar coating program is made up of the alcoholic solution (about 10～30% solids) of resin such as Lac, zein, cellulose acetate phthalate or polyvinyl acetate phthalate usually.Lac preferably uses with the shellac-based dosage form that comprises polyvinylpyrrolidone.The polymer solution that other are suitable as the copolymer (Eudragit ) of Opadry  IR-7000White or dimethylaminoethyl methacrylate and methacrylate, also can be used as sub-coat and uses.

The material that is used to prepare the materia medica enteric coating is known by people.Wherein the most commonly used is the pH sensitive material, and they relatively can not dissolve and permeate under stomach pH, but easier dissolving and infiltration under small intestinal and colon pH.All coating materials that improve active component release according to desirable mode all can use.Particularly, be applicable to that implementing coating material of the present invention includes but not limited to the polymer coating material, as cellulose acetate phthalate, the trimaletate cellulose acetate, Hydroxypropyl Methylcellulose Phathalate, polyvinyl acetate phthalate, methacrylic acid ammonium salt such as Eudragit  RS and RL, polyacrylic acid and polyacrylate and methacrylate copolymer such as Eudragit  S and L, polyvinyl acetal diethylamino acetate (polyvinylacetaldiethylamino acetate), acetic acid succinic acid hydroxypropyl emthylcellulose, Lac; Hydrogel and gel formation material, as CVP Carbopol ETD2050, sodium alginate, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, polyvinyl alcohol, hydroxyethyl-cellulose, methylcellulose, gelatin, starch, the degree of cross linking be low to moderate can impel water to absorb and polymer backbone swollen based on cellulosic cross linked polymer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline Cellulose, chitin, aminoacrylic acid (arninoacryl)-methacrylate copolymer (Eudragit  RS-PM), pulullan polysaccharide (pullulan), collagen protein, casein, agar, arabic gum, sodium carboxymethyl cellulose, polyvinylpyrrolidone, anion and cationic water gel, contain the low residual polyvinyl alcohol of acetate, the swellable mixture of agar and carboxymethyl cellulose, maleic anhydride and styrene, ethylene, the copolymer of propylene or isobutene., pectin, polysaccharide such as agar, arabic gum, POLY-karaya, Tragacanth, Algin and guar gum, polyacrylamide, polyoxyethylene, poly-glucosan diester (diesters of polyglucan), pure and mild poly N-vinyl-the 2-Pyrrolidone of crosslinked polyethylene, gluconic acid Starch Sodium (sodium starchglucolate); Hydrophilic polymer such as polysaccharide, methylcellulose, sodium carboxymethyl cellulose or calcium, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, NC Nitroncellulose, carboxymethyl cellulose, cellulose ether, polyoxyethylene, methylethylcellulose, the ethyl hydroxy ethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen protein, starch, maltodextrin, pulullan polysaccharide, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, fatty glyceride, polyacrylamide, polyacrylic acid, methacrylic acid copolymer or methacrylic acid (for example Eudragit ), other acrylic acid derivatives, Isosorbide Dinitrate, natural gum, lecithin, pectin, alginate, alginic acid ammonia (ammonia alginate), sodium alginate, calcium, potassium, propylene glycol alginate, agar, and natural gum is as arabic gum, POLY-karaya, carob, Tragacanth, carrageenin, guar gum, xanthan gum, scleroglucan and their mixture (mixtures and blends).The thickness of scalable coating provides desirable lag characteristic.Substantially, thicker coating is higher to corrosive resistance, thereby produces longer delay.

In one embodiment of the invention, sub-coat is that (Colorcon, West Point PA), account for about 2.0 weight %～about 5.0 weight % of total composition to Opadry  IR-7000 White.Enteric coating is preferably Acryl-EZE White (Colorcon), accounts for the about 10～14% of total composition, more preferably is about 10%.Colored coating is preferably Opadry  Fx blueness (Colorcon), accounts for about 1.0 weight %～about 3.0 weight % of total composition, more preferably is about 1.5 weight %.

In embodiment preferred of the present invention, sub-coat or sealing coat are OpadrylIR-7000 White, account for about 3.0 weight % of total composition, and enteric coating is preferably Acryl-EZEWhite, account for about 10.0 weight % of total composition.

The absorption of pharmaceutical composition coating embodiment preferably is confined in the intestinal.Pharmaceutical composition optionally be dissolved in the relative intestinal that is alkaline environment effectively.The inventor determined, when two kinds of absolutely different disintegrating agent microcrystalline Cellulose and cross-linked carboxymethyl cellulose are used together, can impel the more rapidly disintegrate of microgranule in intestinal after the peroral dosage form disintegrate.The microcrystalline Cellulose (preferred Avicel PH102) that uses about 11.9 weight % and the cross-linked carboxymethyl cellulose of about 2.0 weight % cause the stripping of compositions faster and dissolution rate is more consistent.

In another embodiment, the invention provides can be used for producing 5 '-premix of pyridoxal 5-phosphate peroral dosage form.5 of powdered '-the pyridoxal 5-phosphate preparation has relatively poor flowability.Therefore, being difficult to mode with unanimity prepares 5 '-the pyridoxal 5-phosphate tablet.Because powdered 5 '-pyridoxal 5-phosphate is difficult for homodisperse, therefore before tabletting, be difficult to 5 '-pyridoxal 5-phosphate and other compositions (being excipient) uniform mixing and make granule.

When hope production contain 5 of high concentration '-during the pyridoxal 5-phosphate tablet, must be with 5 '-pyridoxal 5-phosphate makes granule, with change its physical characteristic it is become can mobile material.For tabletting, good flow behavior is essential, because powder must be able to flow in the sheet nib, therein, powder is stamped into tablet.If powder can not all evenly flow apace, then tablet weight is difficult to control.Relatively poor flow behavior also needs to adopt very slow tabletting speed, and this is unpractical in commerce is used.

One embodiment of the invention provide can be used for producing 5 '-premix of pyridoxal 5-phosphate peroral dosage form, it comprises at least about 5 of 50 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica.

Specific embodiment of the present invention provide can be used for producing 5 '-premix of pyridoxal 5-phosphate peroral dosage form, it comprises 5 of about 82.7 weight % '-pyridoxal 5-phosphate, the microcrystalline Cellulose of about 14.8 weight %, and the cross-linking sodium carboxymethyl cellulose of about 2.5 weight %.The inventor determined, with independent powdered 5 '-pyridoxal 5-phosphate compares, the flow performance of premix make on handling and with active component and other compositions such as but not limited to being more prone on disintegrating agent, binding agent, the mix lubricant.

Can be by in the high speed shear blender, with 5 '-pyridoxal 5-phosphate, microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose mix and prepare premix.

In another embodiment, the invention provides preparation 5 '-method of the peroral dosage form of pyridoxal 5-phosphate enteric coating.Described method comprises that at first will make particle binders such as polyvidone is dissolved in the purified water so that the step of system particle solution to be provided.In a specific embodiments, described method comprises that the polyvidone with about 4.7 weight % is dissolved in the purified water so that the first step of system particle solution to be provided.Polyvidone is preferably the polyvidone of K value between 27～30, more preferably is PVP K30.

Contain 5 by 5 of about 50 weight % '-pyridoxal 5-phosphate powder or the acceptable salt of its materia medica and disintegrating agent or disintegrant mixture such as cross-linking sodium carboxymethyl cellulose being mixed together, preparing '-premix of pyridoxal 5-phosphate.In a specific embodiments, be mixed together by cross-linking sodium carboxymethyl cellulose 5 of about 66.3 weight % '-pyridoxal 5-phosphate (or the acceptable salt of its materia medica) powder and about 11.9 weight % microcrystalline Cellulose and about 2.0 weight %, prepare and contain 5 '-premix of pyridoxal 5-phosphate.Described microcrystalline Cellulose is preferably the microcrystalline Cellulose of the about 0.100mm of particle diameter, and more preferably, described microcrystalline Cellulose is Avicel PH102.Preferably, described premix prepares by the high speed shear blender.The use of high speed shear blender has improved initial stirring and system granule.The use of high speed shear blender has obviously reduced the problem that adopts other types mixture such as ribbon mixer to be brought.Particularly, compare with ribbon mixer, the high speed shear blender does not have " dead band (dead spots) ", thereby makes that stirring is more even.In system granule process, use the high speed shear blender that better control and concordance are provided.In addition, compare with ribbon mixer, the high speed shear blender batch between be easier to the cleaning.Correspondingly, the incidence rate that adopts the high speed shear blender to pollute and change between obviously having reduced batch.

Premix can be mixed together with the system particle solution provides system particulate preparation.Preferably, when premix mixes, the system particle solution is mixed with premix by spraying system particle solution in the high speed shear blender.In other embodiment preferred, adopting and to be furnished with 0.5 " conical ball mill of sieve is to the granular preparation granulate of wet method.Adopt temperature to be set in 60 ℃ fluidized bed dryer then, it is about 1.5% that the granular preparation of gained is dried to water content, and water content wherein is by loss on drying (LOD) test determination.Adopt fluidized bed dryer to have other drying systems such as the not available advantage of hot-blast oven.Use fluidized bed dryer can make granular preparation dry sooner and more even.In case after the granular preparation drying, can adopt the oscillating granulator of being furnished with 20 mesh sieves to described preparation granulate.Make the screen cloth that use is thinner in the granule step in the early stage and can obtain littler granule, this helps granule disintegrate in vivo.In addition, sieve also and to obtain to have the compound particles more uniformly of consistent size.Then, before adding other disintegrating agents, binding agent, lubricant, fluidizer and antitack agent, with the granular preparation of distributed mode agitator (diffusiveblender) stirring through granulate.Preliminary mix dry and through the granule of granulate, for measure by LOD test or Karl Fischer (KF) test water content that provide convenience with sample homogeneous.

Adopt the distributed mode agitator,, mix as microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, Pulvis Talci and colloidal silica and to prepare excipient preparation other excipient.In a specific embodiments, by adopting the distributed mode agitator, the colloidal silica of the Pulvis Talci of the cross-linking sodium carboxymethyl cellulose of the microcrystalline Cellulose of about 9.7 weight %, about 2.0 weight %, about 2.0 weight % and about 0.5 weight % mixed prepare excipient preparation.Colloidal silica very carefully and easily forms agglomerate.By colloidal silica and microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, Pulvis Talci are mixed together, make the colloidal silica densification, thereby help to sieve and prevent heavily agglomeration.At first the mixture of microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, Pulvis Talci and colloidal silica can be passed through 20 mesh sieves, use the distributed mode agitator then they thorough mixing.Then with being furnished with the oscillating granulator of 20 mesh sieves, with gained excipient preparation granulate once more, to smash all agglomerates.

Then can with the distributed mode agitator will be exsiccant, be mixed together through granular preparation granulate and blended and the excipient preparation of granulate, the semi-finished product mixture preparation is provided.In a specific embodiments, then with the distributed mode agitator will be exsiccant, through granular preparation granulate and blended be mixed together through the excipient preparation of granulate, the semi-finished product mixture preparation is provided.

Can be by lubricant such as magnesium stearate be crossed 30 mesh sieve granulate.Can adopt the distributed mode agitator then, will be mixed together the mixture that provides final through the lubricant and the semi-finished product mixture preparation of granulate.Should avoid lubricant and other composition component over-mixed.Usually, lubricant and semi-finished product mixture preparation can be mixed together 3～5 minutes preparation is provided, can avoid over-mixed like this.The peroral dosage form that the over-mixed lubricant is produced has many problems, comprises stripping delay etc.The peroral dosage form that the adding magnesium stearate is produced when stirring end has preferred dissolution characteristic.Preferably, for avoiding taking place over-mixed, lubricant such as magnesium stearate are the components that adds at last in the pharmaceutical preparation.

In a specific embodiments, by the magnesium stearate of about 1.0 weight % being crossed 30 mesh sieve granulate.To be mixed together through the magnesium stearate and the semi-finished product mixture preparation of granulate with the distributed mode agitator then.Usually magnesium stearate and semi-finished product mixture preparation are mixed together 3～5 minutes, so that final press sheet formulation to be provided.

Can press sheet formulation be pressed into label with well known to a person skilled in the art conventional method and equipment then.

Can on label, use sub-coat (or sealing coat) label that is surrounded by sub-coat (or label of sealing) is provided.Can go up enteric coated being surrounded by the label of sub-coat (label of sealing) then.

In a preferred embodiment, use the Opadryl-IR-7000 White dispersion of 5 weight % as sub-coat or sealing coat.On the label of sealing, use enteric coating then.Preferably, use the Acryl EZE White dispersion of 15 weight % as enteric coating.Compare with other enteric coating systems such as Sureteric YAE-6-18107 White, Acryl EZE White provides more superior enteric coating characteristic.Use Acryl EZE White also to have many advantages, as comparing with other enteric coating systems, it is easy to use and handle.By conventional method, can use the coating pan of lateral ventilation perforate or other equipment that is fit to carry out coating.

Below be specific embodiments of the present invention:

In one embodiment of the invention, according to the American Pharmacopeia dissolution test, in the 0.05M of pH6.8 phosphate buffer, described compositions has in the time of 15 minutes and to surpass about 30% dissolution characteristic.

In one embodiment of the invention, according to the American Pharmacopeia dissolution test, in the 0.05M of pH6.8 phosphate buffer, described compositions has in the time of 30 minutes and to surpass about 85% dissolution characteristic.

In one embodiment of the invention, according to the American Pharmacopeia dissolution test, in the 0.05M of pH6.8 phosphate buffer, described compositions has in the time of 45 minutes and to surpass about 90% dissolution characteristic.

In one embodiment of the invention, according to the American Pharmacopeia dissolution test, in the 0.05M of pH6.8 phosphate buffer, described compositions has in the time of 60 minutes and to surpass about 95% dissolution characteristic.

In one embodiment of the invention, according to the American Pharmacopeia dissolution test, in 0.1N HCl, under 37 ℃ and 75rpm, described compositions has in 120 minutes the highest 10% dissolution characteristic.

In one embodiment of the invention, oral absorption 15～60mg/kg compositions produces the maximum blood plasma level (C of 5 of about 1～about 8mg/L '-pyridoxal 5-phosphate in the body between back 2 hours～24 hours of absorption _Max).

In one embodiment of the invention, oral absorption 15～60mg/kg compositions produces 5 of about 0.1～about 2mg/L '-pyridoxal 5-phosphate average plasma levels in the body between back 2 hours～24 hours of absorption.

In one embodiment of the invention, described pharmaceutical composition comprises: (a) label, wherein said label comprise 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica; (b) sub-coat of parcel label; And the enteric coating that (c) wraps up sub-coat.

In one embodiment of the invention, label further comprises the mixture of disintegrating agent or disintegrating agent.Disintegrating agent can be microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose or their mixture.

In one embodiment of the invention, label further comprises the system particle binders.In another embodiment of the invention, described system particle binders is that the K value is 27～33 polyvidone.In one embodiment of the invention, described polyvidone is PVP K-30.

In one embodiment of the invention, microcrystalline Cellulose has the particle diameter of about 0.100mm.

In one embodiment of the invention, microcrystalline Cellulose is Avicel  PH102.

In one embodiment of the invention, sub-coat or sealing coat are Opadry -IR-7000White.

In one embodiment of the invention, the amount of Opadry -IR-7000 White is about 3 weight %.

In one embodiment of the invention, enteric coating is Acryl-EZE White.

In one embodiment of the invention, the amount of Acryl-EZE White is about 10 weight %.

In one embodiment, being used for pharmaceutical composition for oral administration comprises: 5 of about 65 weight %～75 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica, the microcrystalline Cellulose of about 20 weight %～about 30 weight %, the cross-linking sodium carboxymethyl cellulose of about 2.0 weight %～about 4.0%, the polyvidone of about 3.0 weight %～about 6.0 weight %, the Pulvis Talci of about 0.1 weight %～about 4.0 weight %, the colloidal silica of about 0.1 weight %～about 1.0 weight %, and the magnesium stearate of about 0.5 weight %～about 1.5 weight %.

In one embodiment, the invention provides be used to produce 5 '-premix of pyridoxal 5-phosphate peroral dosage form, described premix comprises 5 of about 66.3 weight % '-pyridoxal 5-phosphate.

Embodiment provide prepare 5 '-method of pyridoxal 5-phosphate peroral dosage form, it step that comprises is as follows:

(a) will make particle binders and be dissolved in the purified water, so that the system particle solution to be provided;

(b) 5 of at least 50 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica are mixed with the mixture of disintegrating agent or disintegrating agent, so that premix to be provided;

(c) premix is mixed with the system particle solution, so that granular preparation to be provided;

(d) with granular preparation intensive drying;

(e) excipient is mixed with granular preparation, so that the semi-finished product mixture preparation to be provided;

(f) with semi-finished product mixture preparation and mix lubricant, so that final mixture preparation to be provided;

(g) final mixture preparation is pressed into label;

(h) on label, use sub-coat, so that the label that is surrounded by sub-coat to be provided; And

(i) on the label that is surrounded by sub-coat, use enteric coating.

In one embodiment, the invention provides preparation 5 '-method of pyridoxal 5-phosphate peroral dosage form, its step that comprises is as follows: (a) polyvidone with about 3.0 weight %～about 6.0 weight % is dissolved in the purified water so that the system particle solution to be provided; (b) 5 of about 65 weight %～about 75 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica are mixed with the microcrystalline Cellulose of about 8.0 weight %～about 16.0 weight % and the cross-linking sodium carboxymethyl cellulose of about 1.0 weight %～about 3.0 weight %, so that premix to be provided; (c) described premix is mixed so that granular preparation to be provided with described system particle solution; (d) with described granular preparation intensive drying; (e) about 7.0 weight %～about 14.0 weight % microcrystalline Cellulose, about 1.0 weight %～about 3.0 weight % cross-linking sodium carboxymethyl celluloses, about 1.0 weight %～about 4.0 weight % Pulvis Talci and about 0.1 weight %～about 1.0 weight % colloidal silicas are mixed, so that excipient preparation to be provided; (f) described granular preparation is mixed with described excipient preparation so that the semi-finished product mixture preparation to be provided; (g) described semi-finished product mixture preparation is mixed so that final press sheet formulation to be provided with about 0.5 weight %～about 1.5 weight % magnesium stearate; (h) described press sheet formulation is pressed into label; (i) on label, use sub-coat so that the label that is surrounded by sub-coat to be provided; And (j) use enteric coating in being surrounded by on the sub-coat label, and, randomly, (k) on enteric-coated tablet, use colored coating.

In one embodiment of the invention, described sub-coat is the Opadry  I-IR-7000 White dispersion of about 15%w/v, makes tablet label weight increase about 2.0%～about 5.0% after using.

In one embodiment of the invention, described enteric coating is the Acryl-EZEWhite dispersion of about 20%w/v, makes the tablet label weight that is surrounded by sub-coat increase about 8.0～about 14.0% after using.

In one embodiment of the invention, the Opadry  Blue Fx dispersion that described colored coating is 7.5%w/v makes enteric-coated tablet label weight increase about 1.0～about 3.0% after using.

In one embodiment of the invention, adopt the high speed shear blender with 5 '-pyridoxal 5-phosphate, microcrystalline Cellulose and cross-linked carboxymethyl cellulose mix so that premix to be provided.

In one embodiment of the invention, when described premix mixes,, described system particle solution mixes described premix and described system particle solution on the described premix in described high speed shear blender by being sprayed to.

In one embodiment of the invention, described method also comprises other step: step (c) afterwards and step (d) before, with described granular preparation by being furnished with 0.5 " conical ball mill of screen cloth.

In one embodiment of the invention, adopt inlet temperature to be made as 60 ℃ the dry described granular preparation of fluidized bed dryer.

In one embodiment of the invention, described method comprises other step: step (d) afterwards and step (e) before, described granular preparation by 20 mesh sieves, is mixed described granular preparation then in the distributed mode agitator.

In one embodiment of the invention, described method comprises other step: adopt small-sized distributed mode agitator to mix described premix preparation, then blended premix preparation is passed through 20 mesh sieves.

In one embodiment of the invention, adopt the distributed mode agitator that described granular preparation and premix preparation are mixed.

In one embodiment of the invention, described method is included in mixes the semi-finished product mixture preparation before with the other step of magnesium stearate by 30 mesh sieves with magnesium stearate.

In one embodiment of the invention, adopt the distributed mode agitator that described semi-finished product mixture preparation and magnesium stearate are mixed.

According to 5 '-compositions of pyridoxal 5-phosphate preparation embodiment can join in any suitable dosage form that helps its release.Here the unit label of Miao Shuing can be prepared into granule.Described particle complex (multiparticulate) compositions can be packed in suitable capsule such as hard or the soft capsule.Perhaps, described particle complex compositions (randomly with other excipient) can be pressed into tabloid, can be packed in the capsule then.Another kind of suitable dosage form is a tablet, and wherein said granule is pressed into tablet form.By comprise 5 '-the granuloplastic compositions of pyridoxal 5-phosphate can further be included in the quick stripping dosage form, as effervescent dosage form or instant (fast-melt) dosage form.

Therapeutic Method

In another embodiment, the present invention further provides reduce with oral administration 5 '-method of the incidence rate of the relevant nausea and vomiting of pyridoxal 5-phosphate or the acceptable salt of its materia medica, described method comprise with controlled release, postpone release or controlled release and postpone to discharge mode that combination of oral medication makes up come 5 of effective dosage '-step of pyridoxal 5-phosphate.

The controlled release meaning is meant and anyly makes the release of active substance from dosage form be changed than rapid release product as routine swallow tablet or the slower preparation technique of capsular rate of release.

Postpone to discharge the meaning and be meant that any active substance that makes is changed the preparation technique more late than the release time of conventional rapid release product the release time from dosage form.The follow-up release of active substance from delayed release preparation can also be controlled in a manner described.

This controlled release preparation is preparation as follows preferably, and described mode makes 5 '-pyridoxal 5-phosphate mainly discharges during by the harmonization of the stomach small intestinal, and delayed release preparation preferably is mixed with avoids active substance to discharge under one's belt, and mainly discharges during by small intestinal.Small intestinal can be suitably duodenum, ileum or jejunum.

In a preferred embodiment, described controlled release or delayed release medicine compositions are according to pharmaceutical composition of the present invention, it comprises 5 of about 66.3 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica, about 21.6 weight % microcrystalline Cellulose, about 4.0 weight % cross-linking sodium carboxymethyl celluloses, about 4.7 weight % polyvidones, about 2.0 weight % Pulvis Talci, about 0.5 weight % colloidal silica and about 1.0 weight % magnesium stearate, wherein said compositions is a tablet form, it comprises: (a) label, wherein said label comprise 5 '-pyridoxal 5-phosphate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyvidone, Pulvis Talci, colloidal silica and magnesium stearate; (b) sub-coat of parcel label; And the enteric coating that (c) wraps up described sub-coat.Any coated drugs compositions of the present invention all can be used for reducing with oral administration 5 '-incidence rate of the relevant nausea and vomiting of pyridoxal 5-phosphate or the acceptable salt of its materia medica.

Usually give pharmaceutical composition to treat or to prevent one or more specific indications effectively to measure.Should be understood that and to determine optimal dose according to described indication, its seriousness, route of administration, complication etc. by the standard method that is used for each treatment modalities and indication.The effective dosage of therapeutics further means the amount of the chemical compound that is enough to cause the doing well,improving relevant with described discomfort.The preparation of the application's chemical compound and medicine-feeding technology can be referring to Mack Publishing Co., Easton, the Pa. latest edition " Remington ' s Pharmaceutical Sciences ".For mammal, especially for the mankind's administration, dosage level every day of expected active substance will be 100～1000mg, typically is about 500mg.In any case the doctor can determine the most accurate dosage of suitable certain individuality, and according to age, the body weight of particular individual with reply and change.Above-mentioned dosage is to generally speaking example.Certainly, also may have the individual cases that to adopt higher or lower dosage range, and this dosage range is still within the scope of the invention.

Though the present invention is described by the reference example embodiment, should be appreciated that the present invention is not limited to these accurate embodiments, and can be by those skilled in the art in wherein making various changes and improvements.All this changes and improvements all are considered to be covered by within the appended claim scope.

Embodiment

Embodiment 1-5 '-pyridoxal 5-phosphate enteric coated tablet preparation and preparation method thereof

Listed 5 in the table 1 '-composition and the relative quantity (every 265mg) of pyridoxal 5-phosphate enteric coated tablet preparation.As shown in table 1, produce 20,000 tablets of tablets for one batch.Batch size can be amplified or dwindles by increasing or reduce described relative amount pro rata.

Table 1:5 '-pyridoxal 5-phosphate enteric coated tablet preparation

Composition	％	The mg/ sheet	G/ criticizes
				The system granule stage
5 '-pyridoxal 5-phosphate	66.3	265	5300
				Microcrystalline Cellulose (Avicel PH102)	11.9	47.5	950
Cross-linking sodium carboxymethyl cellulose	2.0	8	160
				Polyvidone (K-30)	4.7	18.75	375
Subtotal:	84.8	339.25	6785
				Purified water (being used for PVP system particle solution) other purified water (being used to make granule)		qs qs	1500 150
The tabletting stage
				The system granule	84.8	339.25	6785
Microcrystalline Cellulose (Avicel PH102)	9.7	38.75	775
				Cross-linking sodium carboxymethyl cellulose	2.0	8	160
Pulvis Talci	2.0	8	160
				Colloidal silica	0.5	2	40
Magnesium stearate	1.0	4	80
				Amount to:	100.0	400	8000
Coating
				Opadry-IR-7000 White (sealing coat)-5% dispersion	3.1	14.1	282
Acryl-EZE White-(enteric coating)-15%	10.2	47.1	942
				Coated tablet amounts to:	100.0	461.2
Purified water (being used for sealing coat)		qs	1598
				Purified water (being used for enteric coating)		qs	5338

5 '-the pyridoxal 5-phosphate enteric coated tablet prepares by following 3 step methods: (1) system granule stage, (2) tabletting stage, and (3) coating phase.Fig. 1～3 have shown the related step of preparation tablet.

System granule and mix stages-by being dissolved in, 30 POVIDONE K 30 BP/USP 30 prepares the system particle solution in an amount of purified water.In high-speed stirring mixer, by with 5 '-microcrystalline Cellulose (Avicel PH102) of pyridoxal 5-phosphate and first deal (first amount) and the cross-linking sodium carboxymethyl cellulose of first deal mix prepared 5 in about 2 minutes '-the pyridoxal 5-phosphate premix.When continuing to mix premix, will make particle solution and be sprayed in the blender.Add remaining required water of system granule method.Described premix was mixed about 5 minutes with the system particle solution, so that granular preparation to be provided.With the gained granule by being furnished with 0.5 " sieve conical ball mill (Comil) granulate.To place the fluid bed that is set under 60 ℃ dry then through the granule of granulate, be about 1.5% until particulate LOD.The Frewitt oscillating granulator that employing is furnished with 20 mesh sieves is to dried granules granulate.Use the distributed mode agitator will be then through the granule stir about of granulate 5 minutes.Adopt the distributed mode agitator, the microcrystalline Cellulose (Avicel PH102) of second deal, cross-linking sodium carboxymethyl cellulose, Pulvis Talci and the colloidal silica of second deal were mixed about 2 minutes, so that excipient preparation to be provided.With described excipient preparation with exsiccant, merge through granulate and blended granular preparation, and in the distributed mode agitator, mixed about 10 minutes, so that the semi-finished product mixture preparation to be provided.To the magnesium stearate granulate, use the distributed mode agitator with 30 mesh sieves then with itself and semi-finished product mixture preparation stir about 5 minutes, so that final press sheet formulation to be provided.

The tabletting stage-adopt rotary tablet machine and plain weave, 11mm, circular, standard, recessed compression mold that described press sheet formulation is pressed into label.

The coating stage-obtain the 5%w/v dispersion in an amount of purified water and prepare sealing coat by Opadryl Y-IR-7000 is scattered in.Use the Opadryl Y-IR-7000 dispersion of capacity, the amount of the feasible Opadryl Y-IR-7000 that is used is about 3.1 weight % with respect to final tablet total weight.Prepare enteric coating by Acryl-EZE White being scattered in the dispersion that obtains 15%w/v in an amount of purified water.Use the Acryl-EZE White of capacity, make that the amount of Acryl-EZE White is about 10.2 weight % with respect to final tablet total weight.Adopting the coating pan of lateral ventilation perforate, is tablet label coating with the sealing coat dispersion at first.Be tablet coating with the enteric coating dispersion then.

The dissolution test of embodiment 2-5 '-pyridoxal 5-phosphate enteric coated tablet and uncoated tablets label

5 '-dissolution characteristic of pyridoxal 5-phosphate enteric coated tablet and uncoated tablets label adopts the routine test method to measure.Dissolution test carries out in being furnished with the VankelModel Vanderkamp 600 of Autosampler, digital thermometer and timer (6 bar) dissolving device.Slurry speed is set in 75rpm.Sample volume is 10ml.According to American Pharmacopeia＜724〉enteric coated tablet method B, implement the stripping program in 2 stages.37 ℃ of acid phases tests of adopting down 0.1N HCl to carry out 120 minutes, under pH6.8 and 37 ℃, carry out the buffer step-by-step test then.

The stripping data of observing enteric coated tablet are within following specification limits:

● in the time of 30 minutes, stripping surpasses 60% in the 0.05M of pH6.8 phosphate buffer;

● in the time of 60 minutes, stripping surpasses 80% in the 0.05M of pH6.8 phosphate buffer; And

● in the time of 120 minutes, stripping is no more than 10% in 0.1N HCl

Fig. 4～7 are line diagram, show the comparison of enteric coated tablet dissolution characteristic and the stripping of tablet label, show that the stripping of tablet is delayed when employing method coating of the present invention.

Fig. 4 shown with low speed use the system particle solution (" granule 1 ") preparation the enteric coating label and the dissolution characteristic of tablet.Before tabletting, it is about 1.5% that granular preparation is dried to water content.

Fig. 5 has shown with the enteric coating label of using system particle solution (" granule 2 ") preparation at a high speed and the dissolution characteristic of tablet.Before tabletting, it is about 1.5% that granular preparation is dried to water content.

Fig. 6 shown with middling speed use the system particle solution (" granule 3 ") preparation the enteric coating label and the dissolution characteristic of tablet.Before tabletting, it is about 1.0% that granular preparation is dried to water content.

Compared granule 1,2 and 3 dissolution characteristic separately among Fig. 7.

Fig. 8 has shown the low, high of granule 1,2 and 3 and has on average discharged percentages.

The dissolution test of embodiment 3-5 '-pyridoxal 5-phosphate enteric coated tablet

Adopt the routine test method to measure the dissolution characteristic of 250mg 5 '-pyridoxal 5-phosphate enteric coated tablet.

Adopt American Pharmacopeia method＜701 〉, in simulated gastric fluid (no pepsin) and simulated intestinal fluid (no pancreatin), measure disintegration time.

In simulated gastric fluid, tablet still remained intact after 1 hour.In simulated intestinal fluid, observe tablet disintegrate fully between 5:46～14:52 minute.

Adopt American Pharmacopeia＜711〉and American Pharmacopeia＜724 enteric coated tablet method B measures dissolution time.The slurry speed of dissolving device is set in 100rpm, and sampled point was set in 30 and 45 minutes.5 '-pyridoxal 5-phosphate concentration in the stripping buffer is measured by LCMS.

The stripping data of observing enteric coated tablet are within following specification limits:

● in the time of 45 minutes, the stripping in the 0.05M of pH6.8 phosphate buffer surpasses 80%; And

● in the time of 120 minutes, the stripping in 0.1N HCl is no more than 10%

In 0.1N HCl, tablet still remained intact after 120 minutes.In the pH6.8 buffer, after 30 minutes, observed stripping is between 91.5%～93.3%.In the pH6.8 buffer, after 45 minutes, observed stripping is between 92.5%～100%.

The safety of embodiment 4-5 '-pyridoxal 5-phosphate enteric coated tablet, toleration and pharmacokinetics test

Implement single center, 1 phase, open label test estimate 5 '-safety, toleration and the pharmacokinetics of pyridoxal 5-phosphate (p5p) enteric coated tablet.

Experimenter-each test group is made up of 6 experimenters (3 male, 3 women), comprising:

● sex, smoker or non-smoker, age 〉=18 and≤55.

● can agree to participate in test.

● BMI 〉=19.0 and＜30.0kg/m ²

The experimenter who meets following arbitrary clause is excluded outside this test:

● before giving trial drug, suffer from disease in 4 weeks with clinical meaning.

● before giving trial drug, carried out having the surgical operation of clinical meaning in 4 weeks.

● any during drug screening, find have the unusual of clinical meaning.

● any thought by medical science assistant researcher the experimenter should be got rid of reason outside test.

● be judged unusual lab testing with clinical meaning.

● hepatitis B, hepatitis C or HIV check and are positive when screening.

● in when screening ECG unusual (having clinical meaning) or vital signs unusual (systolic pressure is lower than 100 or be higher than 140mmHg, and diastolic pressure is lower than 60 or be higher than 90mmHg, and perhaps heart rate is less than 60 or greater than 100bpm).

● in screening was made a house call preceding 1 year, tangible alcohol abuse history or drug dependence history are arranged.

● in screening was made a house call preceding 6 months, often drink (ethanol [1 unit=150mL wine, 360mL medicated beer, the perhaps ethanol of 45mL 45%] that surpasses 14 units weekly).

● in screening was made a house call preceding 3 months, use soft drug (as Fructus Cannabis) or in screening was made a house call preceding 1 year, used hard drug (as ***e, phencyclidine [PCP] and KUAIKE (crack)) or the urine medicine inspection is positive in when screening.

● to heparin, 5 '-the anaphylaxis history of pyridoxal 5-phosphate, vitamin B6, other pyridoxol class materials or other related drugs.

● used in preceding 30 days and anyly knownly induce or suppress the metabolic medicine of liver medicine (derivant example: barbiturate, carbamazepine, phenytoin, glucocorticoid, omeprazole giving trial drug; Inhibitor example: antidepressants (SSRI), Cimetidine, diltiazem, Macrolide, imidazoles, Antipsychotic drug, verapamil, fluoroquinolones, antihistaminic).

● used the research medicine or participated in development test in preceding 30 days giving trial drug.

● have the following medical history of clinical meaning or have any gastrointestinal tract pathology (for example chronic diarrhea, inflammatory bowel), delay property (unresolved) gastrointestinal symptom (for example suffer from diarrhoea, vomit), liver or kidney disease, perhaps other known interference medicament absorptions, distribution, metabolism or excretory disease with clinical meaning.

● any nerve, endocrine, cardiovascular, lung, blood, immunity, psychosis or metabolic disease that has the following medical history of clinical meaning or have clinical meaning.

● used prescription drug in preceding 14 days or giving trial drug and used over-the-counter drug (comprise wholefood enriching substance, vitamin, as the Bulbus Allii of enriching substance) in preceding 7 days giving trial drug, do not have except the topical products or hormonal contraceptive that whole body absorbs.

● smoking every day surpasses 25 medicated cigarettes.

● any by medical science assistant researcher think may show that the experimenter should not participate in the food anaphylaxis of this test, do not tolerate, dietary restriction or special diet.

● depot injection or implant any medicine (except the hormonal contraceptive) in giving preceding 3 months of trial drug.

● contribute blood plasma (500mL) in administration in preceding 7 days.The whole blood (except the blood volume that extracts during this experiment sieving program) of contributing before giving trial drug or losing is as follows:

Zero in preceding 30 days of administration 50mL～300mL whole blood,

Zero in preceding 45 days of administration 301mL～500mL whole blood, perhaps

Zero surpasses the 500mL whole blood in preceding 56 days of administration.

● the experimenter of breast feeding.

● the urine pregnancy tests positive when screening.

● in giving preceding 14 days of trial drug with the female subjects with fertility of any not sterillization man companion (promptly not by at least 6 months male of vasectomy sterillization) generation Unprotected coitus.Acceptable contraceptive device has:

Zero intra-uterine contraceptive device (at least 4 weeks placed before giving trial drug);

Zero condom or contraceptive membrane+spermicide;

Zero hormonal contraceptive (at least 4 weeks began to take before giving trial drug).

Restriction-experimenter is required to restrain: smoking between 6 hours to the administration at least 2 hours before administration;

● between preceding 24 hours of administration is to last sample collecting, drink alcoholic product;

● edible or drink food or the beverage that contains the relevant chemical compound of xanthine derivative or xanthine between preceding 48 hours of administration is to last sample collecting;

● between preceding 7 days of administration is to last sample collecting, take vitamin and wholefood enriching substance;

● table grapes Fructus Citri grandis product between preceding 7 days of administration is to last sample collecting.

Between preceding 48 hours of administration was to last test specimen collection, the experimenter was required to avoid edible or drinks food or the beverage that contains the high concentration vitamin B6.The Food ﹠ Drink of avoiding comprise big bean products, whole wheat and Testa Tritici product, Fructus Musae, nut, Rhizoma Solani tuber osi, Radix Dauci Sativae juice, dried plum juice, malted milk, fish and Hepar Gallus domesticus.

Do not carry out the male of surgical sterilization or male that the spouse has fertility and must be willing to be intended to duration of test and use condom to add spermicide in 14 days after the trial drug administration the last time, and/or guarantee that their spouse uses effective contraceptives in phase in the same time.

Note the medicated cigarette number of between whole restricted period, inhaling, be no more than 25 in duration of test (inhouse) smoking every day to guarantee the experimenter.

Have fertility and the female subjects of sexual intercourse takes place with the male spouse of not sterillization, be required before giving trial drug, after giving last trial drug, to use during 14 days acceptable contraceptive device.On acceptable contraceptive device is seen.

Demography data, medical treatment and pharmacohistory, physical examination, somatometry (for example height, weight and stature), ECG, vital signs, hematology, biochemistry, HIV, hepatitis B and hepatitis C, urinalysis, urine medicine inspection and the urine pregnancy tests of experimenter's screening sequence-to the experimenter in giving preceding 28 days of trial drug are screened.

Trial drug-5 '-pyridoxal 5-phosphate monohydrate enteric coated tablet, accumulated dose 250mg (CanAm Bioresearch Inc., Canada).

Restriction, make a house call and administration-before administration, extracted behind the blood in 24.0 hours to the administration at least 12 hours between, experimenter's action is restricted.The experimenter will return and carry out follow-up blood draw.Every experimenter takes trial drug with 300mL water, checks subject oral cavity, to guarantee that medicine is taken.

Concomitant drugs-except that the experimenter uses the concomitant drugs because of adverse events, duration of test does not allow to use concomitant drugs.Except that using hormonal contraceptive and using once in a while the acetaminophen, the use of any concomitant drugs is estimated one by one through titular researcher or doctor.

Blood sample gathers and handles-from every experimenter, extract totally 19 parts of blood samples, be used for the quantitative of P5P (5 '-pyridoxal 5-phosphate), PAL (2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine .) and PA (4-Pvridoxic Acid).Before administration, gathered blood samples (each sampling time point is gathered 10mL) in the EDTA blood taking tube after 10,1 and 0.25 hours and the administration in 1.00,2.00,3.00,3.50,4.00,4.50,5.00,5.50,6.00,7.00,8.00,10.00,12.00,14.00,24.00 and 36.00 hours.Except as otherwise noted or for experimenter's safety reasons, when blood draw and other program conflicts, preferentially extract blood.As possible, before administration to the administration the blood sample between 14 hours (or more late) by the collection of dead volume (dead-volume) indwelling venous catheter; If, then gather blood sample by direct venipuncture not by the intubate collection.

That gathers from every group every experimenter comprises that gathering the blood cumulative volume that is used for selected qualification and safety purpose must not surpass 237mL.Only when the blood cumulative volume of whole test is exceeded, report that just blood volume departs from.

Urine sample collection and processing-for carry out P5P, PAL and PA quantitatively, in 6 periods or interval, gather urine sample: before administration and after the administration 0.00～4.00,4.00～8.00,8.00～12.0,12.0～24.0 and 24.0～36.0 hour.In preceding 2 hours of administration, collect sample before the administration.The experimenter is required the urine in their bladder of emptying in preceding 15 minutes of administration so that they begin at interval nextly under empty bladder state, and finished the urine in their bladder of emptying in back 15 minutes at interval at 12.0～24.0 hours.For 24.0～36.0 hours interval after the administration, provide urine container to the experimenter, require them to collect the urine of all theirs at home and note the time of collecting urine.The experimenter accepts how correctly to collect and preserve the guidance of urine sample.In the predetermined day of making a house call of returning, they are required all urine samples are taken back outpatient service.Urine during returning make a house call (in 15 minutes after finishing from described interval) is collected too.All urines that the experimenter discharges in two cross points, interval (in 10 minutes) are included in the last duplicate samples.Note urine that all experimenters discharge but that be not collected.

Food and fluid take in-before administration, forbade feed between at least 4 hours to the administration at least 10 hours.Thereafter in due course between for the experimenter provide through control diet.Between restricted period, all diet are all controlled the content of vitamin B6 in action.Avoid taking in F﹠B (on seeing) with high concentration vitamin B6.Except being used to take the water of trial drug, forbid drinking-water between 2 hours to the administration preceding 2 hours of administration.Can free drinking water in all the other times.

Experimenter's safety-during whole test, the adverse events of trial drug and/or program is come the experimenter is monitored by the monitoring experimenter.Before administration with administration after measured in about 1,2,4,6,12 hour the experimenter when the sitting posture blood pressure, heart rate, breathing rate and the oral temperature of (unless for safety reasons) (when vital signs are measured when identical with the blood draw time, whenever possible, preferred arrangement they before blood draw, carry out).Before administration with administration after about 1,2,4,6 with 12 hours ECG that lie on the back (when ECG was identical with the blood draw time, whenever possible, they carried out preferred arrangement behind blood collection as far as possible as early as possible).When following situation occurring, vital signs of repeated measure at least:

1) predetermined systolic pressure is measured less than 90mmHg, perhaps is higher than 140mmHg;

2) predetermined diastolic pressure is measured less than 50mmHg, perhaps is higher than 90mmHg;

3) Yu Ding heart rate is lower than 50bpm, perhaps is higher than 100bpm; Perhaps

4) according to doctor's requirement.The doctor must be noted that all repeated measure but still exceeds the vital signs measured value of above-mentioned normal range value, make an appraisal with importance to the result, if necessary, and decision only a walking is moving.

Before administration, carry out hematology, biochemistry, urinalysis, urine medicine inspection and serum pregnancy check.

Hematology, biochemistry, urinalysis, physical examination, vital signs, ECG, urine pregnancy test and adverse events monitoring are carried out in test of test back program-in the end day or the 14th day after the experimenter participates in testing at last the latest.

Safety and toleration parameter-come evaluate safety and toleration by estimating lead ECG, clinical laboratory's parameter and physical examination of adverse events, vital signs, 12.Adverse events is listed with form.

Pharmacokinetic parameter-the calculate following pharmacokinetic parameter of P5P, PAL and PA by the non-atrioventricular method of standard:

● plasma sample is used to calculate following parameter:

1) C _Max: observed Cmax

2) T _Max: the observed C that reaches _MaxTime

3) K _El: elimination rate constant

4) T _1/2el: eliminate the half-life

5) AUC _0-t: from zero area under the concentration-time curve up to last non-zero concentration

6) AUC _0-inf: from zero area under the concentration-time curve up to infinitely great (extrapolation)

7) AUC _T/inf: AUC _0-tWith AUC _0-infThe ratio

8) Cl/F: CLTB, by dosage/AUC _0-infCalculate

9) V _d/ F: apparent volume of distribution, by dosage/(K _El* AUC _0-inf) calculate

10) MRT: mean residence time

● urine sample will be used to calculate following parameter:

1) accumulation urine excretion (Ae _0-t).

Statistical analysis-being described property statistical analysis.

Baseline correction: because P5P comprises the endogenous concentration of taking in from vitamin B6, therefore adopting simultaneously has baseline correction and no baseline correction to analyze.Every experimenter is proofreaied and correct with the average result of this identical experimenter plasma sample that (preceding 10,1 and 0.25 hours of administration) obtains before administration.If after correction, draw negative concentration results, then concentration is made as and equals zero.

List single among result-table 1 and taken P5P, PAL behind the 250mg dosage enteric coating P5P and average blood plasma and the urine concentration of PA.

The blood plasma and the urine concentration of table 1-P5P and metabolite

The sample of analyzing	C max(ng/ml±SE)	T max(hr±SE)
			Blood plasma P5P	371.3±86.4	3.2±0.5
Blood plasma PAL	1971.0±113.8	3.8±0.5hr
			Blood plasma PA	3372.3±314.4	3.8±0.5hr
Urine P5P	325.0±32.3	4.0～36.0hr
			Urine PAL	5255.1±999.6	0.0～8.0hr

Only adverse events of duration of test report be an example in the morning during 8:55 a slight drowsiness report and an example at noon during 12:00 in the report of tailbone region mild pain.The report adverse events rare degree and slightly show P5P under 250mg dosage safety with can tolerate.

Among 6 patients 2 reported adverse events (at the oral 250mg of 7:00am) same day in administration.Experimenter is at slight drowsiness of 8:55am report, and experimenter 12:00 at noon is reported in tailbone region and mild pain occurs.Researcher thinks that drowsiness might be relevant with Drug therapy, and thinks irrelevant at the pain and the medicine of tailbone region.The report adverse events rare degree and slightly show P-5-P under the 250mg oral dose safety with can tolerate.

Claims (78)

1. One kind be suitable for 5 of oral administration '-pyridoxal 5-phosphate pharmaceutical preparation, when according to the American Pharmacopeia dissolution test, in the standard dissolving device, in the 0.05M of pH6.8 phosphate buffer, when measuring under 37 ℃ and 75rpm, it comprises following dissolution characteristic:

   A) in the time of 15 minutes, surpass about 30%,

   B) in the time of 30 minutes, surpass about 85%,

   C) in the time of 45 minutes, surpass about 90%, perhaps

   D) in the time of 60 minutes, surpass about 95%.
2. 2. one kind 5 '-pyridoxal 5-phosphate pharmaceutical preparation, when according to the American Pharmacopeia dissolution test, in the standard dissolving device, when measuring under 37 ℃ and 75rpm in 0.1N HCl, its dissolution characteristic that comprises is for the highest by 10% in 120 minutes.
3. 3. 5-pyridoxal 5-phosphate pharmaceutical preparation, wherein oral absorption 15～60mg/kg produces the maximum blood plasma level (C of 5 of about 1～about 8mg/L '-pyridoxal 5-phosphate in the body _Max).
4. 4. as each pharmaceutical preparation in the claim 1～3, wherein tablet comprises: (a) label, wherein said label comprise 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica; (b) sub-coat of the described label of parcel; And the enteric coating that (c) wraps up described sub-coat, and randomly, (d) the colored coating of parcel enteric coating.
5. 5. pharmaceutical preparation as claimed in claim 4, wherein said label further comprises the mixture of disintegrating agent or disintegrating agent.
6. 6. pharmaceutical preparation as claimed in claim 5, the mixture of wherein said disintegrating agent or disintegrating agent comprises microcrystalline Cellulose.
7. 7. pharmaceutical preparation as claimed in claim 6, wherein said microcrystalline Cellulose has the particle diameter of about 0.100mm.
8. 8. as the pharmaceutical preparation of claim 6 or 7, wherein said microcrystalline Cellulose is Avicel PH102.
9. 9. as each pharmaceutical preparation in the claim 4～7, wherein said label further comprises polyvidone.
10. 10. pharmaceutical preparation as claimed in claim 9, the K value of wherein said polyvidone is between 27～33.
11. 11. as the pharmaceutical preparation of claim 10, wherein said polyvidone is PVP K30.
12. 12. as each pharmaceutical preparation in the claim 4～11, wherein said sub-coat is Opadry ^-IR-7000 White.
13. 13. as the pharmaceutical preparation of claim 12, wherein said Opadry ^The amount of-IR-7000White is about 3 weight %.
14. 14. as each pharmaceutical preparation in the claim 4～13, wherein said enteric coating is Acryl-EZE White.
15. 15. as the pharmaceutical preparation of claim 14, wherein the amount of Acryl-EZE White is about 10～12 weight %.
16. 16. as the pharmaceutical preparation of claim 15, wherein the amount of Acryl-EZE White is about 10 weight %.
17. 17. as each pharmaceutical preparation in the claim 4～16, wherein said label further comprises lubricant.
18. 18. as the pharmaceutical preparation of claim 17, wherein said lubricant is a magnesium stearate.
19. 19. as each pharmaceutical preparation in the claim 4～18, wherein said disintegrating agent or disintegrant mixture comprise cross-linking sodium carboxymethyl cellulose.
20. 20. as each pharmaceutical preparation in the claim 4～19, wherein said disintegrating agent or disintegrant mixture comprise microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose.
21. 21. as each pharmaceutical preparation in the claim 4～20, wherein said label further comprises Pulvis Talci.
22. 22. as each pharmaceutical preparation in the claim 4～21, wherein said label further comprises colloidal silica.
23. 23. as each pharmaceutical preparation in the claim 1～22, wherein said preparation comprises 5 of at least 50 weight % '-pyridoxal 5-phosphate.
24. 24. as the pharmaceutical preparation of claim 23, wherein said preparation comprises 5 between about 60 weight %～about 70 weight % '-pyridoxal 5-phosphate.
25. 25. as the pharmaceutical preparation of claim 24, wherein said preparation comprises 5 of about 66.3 weight % '-pyridoxal 5-phosphate.
26. 26. pharmaceutical preparation as claimed in claim 4, it comprises: 5 of about 65 weight %～about 75 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica, the microcrystalline Cellulose of about 20 weight %～30 weight %, the cross-linking sodium carboxymethyl cellulose of about 2.0 weight %～about 4.0 weight %, the polyvidone of about 3.0 weight %～about 6.0 weight %, about 1.0 weight %～about 4.0 weight % Pulvis Talci, the colloidal silica of about 0.1 weight %～about 1.0 weight %, and the magnesium stearate of about 0.5 weight %～about 1.5 weight %.
27. 27. pharmaceutical preparation as claimed in claim 4, it comprises: 5 of about 66.3 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica, the microcrystalline Cellulose of about 21.6 weight %, the cross-linking sodium carboxymethyl cellulose of about 4.0 weight %, the polyvidone of about 4.7 weight %, the Pulvis Talci of about 2.0 weight %, the colloidal silica of about 0.5 weight %, and the magnesium stearate of about 1.0 weight %.
28. 28. as each pharmaceutical preparation in the claim 4～27, wherein said colored coating is Opadry  Blue Fx.
29. 29. as the pharmaceutical preparation of claim 28, the Opadry  Blue Fx dispersion that wherein said Opadry  Blue Fx is about 7.5w/v.
30. 30. as the pharmaceutical preparation of claim 28, wherein said pharmaceutical composition comprises the Opadry  Blue Fx of about 1.0～3.0 weight %.
31. 31. pharmaceutical preparation as claimed in claim 3, the wherein C of 5-pyridoxal 5-phosphate _MaxBetween about 0.1～2mg/L.
32. 32. be used to prepare 5 '-premix of pyridoxal 5-phosphate peroral dosage form, it comprises at least about 5 of 50 weight % '-pyridoxal 5-phosphate.
33. 33. as the premix of claim 32, wherein said premix further comprises microcrystalline Cellulose.
34. 34. as the premix of claim 32 or 33, wherein said premix further comprises cross-linking sodium carboxymethyl cellulose.
35. 35. as the premix of claim 34, it comprises: 5 of about 82.7 weight % '-pyridoxal 5-phosphate, the microcrystalline Cellulose of about 14.8 weight %, and the cross-linking sodium carboxymethyl cellulose of about 2.5 weight %.
36. 36. as each premix in the claim 33～35, wherein said microcrystalline Cellulose has the particle diameter of about 0.100mm.
37. 37. as each premix in the claim 33～36, wherein said microcrystalline Cellulose is Avicel PH102.
38. 38. as each premix in the claim 32～37, wherein said premix further comprises the polyvidone of K value between 27～33.
39. 39. as the premix of claim 38, wherein said polyvidone is PVP K-30.
40. 40. one kind prepare 5 '-method of pyridoxal 5-phosphate peroral dosage form, it may further comprise the steps:

    A) will make particle binders and be dissolved in the purified water, so that the system particle solution to be provided;

    B) 5 of at least 50 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica are mixed with disintegrating agent or disintegrant mixture, so that premix to be provided;

    C) described premix is mixed so that granular preparation to be provided with described system particle solution;

    D) with described granular preparation intensive drying;

    E) excipient is mixed with described granular preparation, so that the semi-finished product mixture preparation to be provided;

    F) with described semi-finished product mixture preparation and mix lubricant, so that final mixture preparation to be provided;

    G) described final mixture preparation is pressed into label;

    H) on label, use sub-coat, so that the label of sub-coat to be provided; And

    I) on the label of sub-coat, use enteric coating.
41. 41. as the method for claim 40, wherein said disintegrating agent or disintegrant mixture comprise microcrystalline Cellulose.
42. 42. as the method for claim 41, wherein said microcrystalline Cellulose has the particle diameter of about 0.100mm.
43. 43. as the method for claim 41 or 42, wherein said microcrystalline Cellulose is Avicel PH102.
44. 44. as each method in the claim 40～43, wherein said disintegrating agent or disintegrant mixture comprise cross-linking sodium carboxymethyl cellulose.
45. 45. as the method for claim 44, wherein said disintegrating agent or disintegrant mixture comprise microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose.
46. 46. as the method for claim 45, wherein said premix comprises the microcrystalline Cellulose of about 8.0 weight %～about 20 weight % and the cross-linking sodium carboxymethyl cellulose of about 1.0 weight %～about 4.0 weight %.
47. 47. as each method in the claim 40～46, wherein said system particle binders comprises the polyvidone of K value between 27～33.
48. 48. as each method in the claim 40～47, wherein said system particle binders comprises the polyvidone of about 4.7 weight %.
49. 49. as the method for claim 47 or 48, wherein said polyvidone is PVP K-30.
50. 50. as each method in the claim 40～49, wherein said sealing coat is the Opadry of about 15%w/v ^I-IR-7000 White dispersion.
51. 51. as each method in the claim 40～50, wherein said enteric coating is the Acryl-EZE White dispersion of about 20%w/v.
52. 52. as each method in the claim 45～51, wherein mix with the high speed shear blender described 5 '-pyridoxal 5-phosphate, microcrystalline Cellulose and cross-linked carboxymethyl cellulose, so that premix to be provided.
53. 53. as the method for claim 52, wherein said premix and system particle solution are mixed by described system particle solution is sprayed on the described premix when described premix is mixed in the high speed shear blender.
54. 54. as each method in the claim 40～53, its step (c) afterwards and step (d) further comprise before described granular preparation by being furnished with 0.5 " step of the conical ball mill of sieve.
55. 55. as each method in the claim 40～54, it is dry that wherein said granular preparation adopts 60 ℃ fluidized bed dryer.
56. 56. as each method in the claim 40～55, its step (d) afterwards and step (e) further comprise before described granular preparation and in the distributed mode agitator, to mix the step of described granular preparation then by 20 mesh sieves.
57. 57. as each method in the claim 40～56, it further comprises with small-sized distributed mode agitator described premix is mixed, then with the step of blended premix by 20 mesh sieves.
58. 58. as each method in the claim 40～57, wherein said granular preparation and premix adopt the distributed mode agitator to mix, with preparation semi-finished product mixture preparation.
59. 59. as each method in the claim 40～58, its with lubricant with further comprise the step of lubricant before the semi-finished product mixture preparation mixes by 30 mesh sieves.
60. 60. as each method in the claim 40～59, wherein said semi-finished product mixture preparation and lubricant adopt the distributed mode agitator to mix.
61. 61. as each method in the claim 40～60, wherein said lubricant is a magnesium stearate.
62. 62. as each method in the claim 40～61, wherein the excipient of step (e) comprises colloidal silica.
63. 63. as each method in the claim 40～62, wherein the excipient of step (e) comprises the colloidal silica of about 0.5 weight %.
64. 64. as each method in the claim 40～63, wherein the excipient of step (e) comprises Pulvis Talci.
65. 65. as each method in the claim 40～64, wherein the excipient of step (e) comprises the Pulvis Talci of about 2 weight %.
66. 66. as each method in the claim 40～65, wherein the excipient of step (e) comprises disintegrating agent or disintegrant mixture.
67. 67. as the method for claim 66, wherein said disintegrating agent or disintegrant mixture comprise microcrystalline Cellulose.
68. 68. as the method for claim 66, wherein said disintegrating agent or disintegrant mixture comprise cross-linking sodium carboxymethyl cellulose.
69. 69. as the method for claim 66, wherein said disintegrating agent or disintegrant mixture comprise microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose.
70. 70. as each method in the claim 40～69, wherein the excipient of step (e) comprises the microcrystalline Cellulose of about 8.0 weight weight %～about 20 weight % and the cross-linking sodium carboxymethyl cellulose of about 1.0 weight %～about 4.0 weight %.
71. 71. as each method in the claim 40～70, wherein the excipient of step (e) comprises the microcrystalline Cellulose of about 8.0 weight weight %～about 12.0 weight %, the cross-linking sodium carboxymethyl cellulose of about 1.0 weight weight %～about 4.0 weight %, the Pulvis Talci of about 1.0 weight weight %～about 4.0 weight %, and the colloidal silica of about 0.1 weight weight %～about 1.0 weight %.
72. 72. as each method in the claim 40～71, wherein said 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica is between about 60 weight weight %～about 70 weight %.
73. 73. as each method in the claim 40～72, wherein said 5 '-pyridoxal 5-phosphate or the acceptable salt of its materia medica are about 66.3 weight %.
74. 74. as each method in the claim 40～73, wherein said step comprises:

    A) polyvidone with about 4.7 weight % is dissolved in the purified water, so that the system particle solution to be provided;

    B) 5 of about 66.3 weight % '-pyridoxal 5-phosphate or the acceptable salt of its materia medica are mixed with the microcrystalline Cellulose of about 11.9 weight % and the cross-linking sodium carboxymethyl cellulose of about 2.0 weight %, so that premix to be provided;

    C) described premix is mixed so that granular preparation to be provided with described system particle solution;

    D) with described granular preparation intensive drying;

    E) Pulvis Talci of the cross-linking sodium carboxymethyl cellulose of the microcrystalline Cellulose of about 9.7 weight %, about 2.0 weight %, about 2.0 weight % and the colloidal silica of about 0.5 weight % are mixed, so that the premix preparation to be provided;

    F) described granular preparation and described premix preparation are mixed, so that the semi-finished product mixture preparation to be provided;

    G) described semi-finished product mixture preparation is mixed with the magnesium stearate of about 1.0 weight %, so that press sheet formulation to be provided;

    H) described press sheet formulation is suppressed the heart in blocks;

    I) use sub-coat in the heart so that the sheet heart of sub-coat to be provided in sheet; And

    J) use enteric coating in the heart in the sheet of sub-coat.
75. 75. a reduction and oral administration 5 '-method of the incidence rate of the nausea and vomiting that pyridoxal 5-phosphate or the acceptable salt of its materia medica are relevant, it comprises the step as each pharmaceutical composition in the claim 1～31 of effective dosage.
76. 76. as in the claim 1～31 each pharmaceutical composition reduce with oral administration 5 '-application in the incidence rate of the relevant nausea and vomiting of pyridoxal 5-phosphate or the acceptable salt of its materia medica.
77. 77. one kind increases the method that needs with the patient's of 5-pyridoxal 5-phosphate treatment compliance, it comprise effective dosage as each pharmaceutical composition in the claim 1～34.
78. 78. as each the application of pharmaceutical composition in the patient's who improve to need uses the treatment of 5-pyridoxal 5-phosphate compliance in the claim 1～31.

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