CN101528200A - Dry granulation binders, products, and use thereof - Google Patents

Abstract

The invention discloses a method for the preparation of microcrystalline cellulose containing tablets by roller compaction followed by tabletting. A tablet formulation is converted to a dry granulate by roller compaction, and the dry granulate lubricated dry granulate and compacted to a tablet. The tablet formulation comprises at least one active, an microcrystalline cellulose containing material, and, optionally other pharmaceutically acceptable excipients. The microcrystalline cellulose containing material has a maximum primary compaction tensile strength of at least 9 MPa or at least 9.5 MPa and a secondary compaction tensile strength of at least 5 MPa, at least 5.5 MPa, or at least 6 MPa.

Description

Dry granulation binders, product and uses thereof

The cross reference of related application

The application requires in the U.S. Provisional Application serial number 60/855 of submission on October 27th, 2006,106, the U.S. Provisional Application serial number 60/928 that on May 8th, 2007 submitted to, 166, with the U.S. Provisional Application serial number of submitting on October 27th, 2,006 60/855,066 priority, the content of above-mentioned provisional application all are incorporated into this paper by reference.

Invention field

The present invention relates to dry granulation binders, this binding agent has and is used for by repeatedly compressing the high compactability again (recompactability) that legal system is equipped with solid dosage forms.Particularly, the present invention relates to the microcrystalline Cellulose based adhesive, above-mentioned binding agent guarantees good granulate quality, and enough granules are compactability again, to obtain the tablet of required hot strength.

Background of invention

The discrete dosages that is fit to oral pharmaceutical composition is with solid dosage forms, and normally tablet is taken easily.Except one or more therapeutic components (so-called " active component ", " active medicine component " or " API ") outside, tablet comprises pharmaceutically acceptable material (being called excipient), these materials are not active components, therapeutical effect is not provided, but is added in the tablet to make it to have and the irrelevant special properties of activity of active component.

Usually method for preparing tablet thereof has following three kinds: (1) is compacting directly; (2) dry granulation; (3) wet granulation.In direct compacting, the dusty material (comprising active component and excipient) that tablet comprises is blended together, and do not need intermediate treatment such as pelletization and directly compacting.Though directly compacting is the effective and the most favourable manufacture method of preparation solid dosage forms such as tablet, many tablet formulations can not use direct pressing die processing.

Film-making situation that got rid of by direct compacting can adopt granulating process because the flowability of the mixture of direct compacting is poor or bulk density is low.Granulate and also improved the content uniformity of active component, reduce dust and produce.Dry granulation comprises mixes component, and mixture roll-in or tablet is prefabricated, and dry sieving or to grind be the coarse granule of doing is lubricated and with lubricated granule compacting.The wet granulation method comprises mixes part component or all components, adds the solution of binding agent then in blended powder.With the wet material screening of making, drying, lubricated and compacting is in flakes.

In dry granulation, tablet ingredients is contact wetting not, solvent and heat.Therefore, can be used to processing to humidity, solvent and/or heat sensitive active component.Dry granulation can be by tablet prefabricated or roll-in carry out.Tablet is prefabricated to be a kind of double compression method.The material of making tablet is pressed into bigger compacting thing or " pre-tabletting ", changes tablet into by the secondary pressing process then.Because tablet is prefabricated is slow and uneconomic method, and roll-in becomes carries out the dry granulation method selected.Roll-in have granulating process benefit, as improving the flow behavior and the content uniformity of material.In addition, specific energy a large amount of and operate more economically mutually for roll operation and wet granulation.

In rolling process, the high pressure roller by two reverse rotations compresses the tablet formulations (" granule formulations ") of at least a portion and densification, and the material of making is crushed to single-size.The granule of making can form tablet adding excipient or not having film-making under the excipient condition subsequently.By the formation tablet of exerting pressure on the tablet formulations in the punch die of tablet machine.Tablet machine comprises and is assemblied in the low punch the punch die from the bottom and has respective shapes and the upper punch of size, is filled at tablet formulations that the back upper punch enters die cavity from the top in the die cavity.Tablet formulations in punch die is exerted pressure and is formed sheet by low punch and upper punch.

Microcrystalline Cellulose (MCC) is widely used as excipient because of its inherent compactability characteristics in pharmaceutical preparation.When being used for tablet formulations, MCC can also obtain good bonding and disintegrative.

The process that forms tablet by roll-in film-making subsequently comprises two compaction step.But after first compaction step, it is that the film-making step may not have enough compactability that the MCC granule compresses second.Therefore, still need a kind of binding agent that contains crystallite, this binding agent can be used for by comprising the ready-formed prepared solid dosage forms of a plurality of compaction step such as roll-in and film-making or tablet.Described binding agent must have enough compactability to second compaction step.

Summary of the invention

The invention provides a kind of binding agent that contains microcrystalline Cellulose that improves again compactability that has, this binding agent can be used for preparing solid dosage forms by the multistep impacted process.An aspect, the invention provides a kind of compositions, said composition comprises at least 60 weight % and contains the microcrystalline cellulose cellulosic material, the elementary hot strength of said composition after the primary compaction of 250MPa is at least 9.5MPa, is at least 5.5MPa in the tensile strength after carrying out secondary compaction under the 250MPa after the primary compaction of 250MPa.Another aspect, the invention provides a kind of adhesive composition, said composition comprises at least 60 weight % and contains the microcrystalline cellulose cellulosic material, the elementary hot strength of this adhesive composition after the primary compaction of 250MPa is at least 9.0MPa, be at least 5.0MPa in the tensile strength after carrying out secondary compaction under the 250MPa after the primary compaction of 250MPa, wherein contain the MCC material and be microcrystalline Cellulose with the material coprocessing that is selected from sugar alcohol or carboxymethyl cellulose.

Another aspect, the invention provides a kind of adhesive composition, said composition comprises at least 60 weight % and contains the microcrystalline cellulose cellulosic material, the elementary hot strength of adhesive composition after the primary compaction of 250MPa is at least 9.5MPa, is at least 6.0MPa in the tensile strength after carrying out secondary compaction under the 250MPa after the primary compaction of 250MPa.In yet another aspect, the material that contains MCC is the microcrystalline Cellulose with the material coprocessing that is selected from sugar alcohol or carboxymethyl cellulose.

In yet another aspect, the invention provides a kind of adhesive composition, said composition comprises at least 60 weight % and contains the microcrystalline cellulose cellulosic material, the maximum secondary hot strength of described adhesive composition after carrying out secondary compaction after the primary compaction of 250MPa is at least 6.5MPa, wherein, the material that contains MCC is the microcrystalline Cellulose with the material coprocessing that is selected from sugar alcohol or carboxymethyl cellulose.

Comprise the granular preparation that contains the microcrystalline Cellulose binding agent of the present invention, granule, solid dosage forms and tablet also all are aspects of the present invention.In other respects, the present invention includes preparation and comprise the granular preparation that contains the microcrystalline Cellulose binding agent of the present invention, granule, the method for solid dosage forms and tablet.In yet another aspect, the invention provides test, estimate and select binding agent, especially comprise at least about 40 weight, or at least about 60 weight %, or at least about the method for the binding agent that contains the microcrystalline cellulose cellulosic material of 65 weight %, to determine to have the binding agent of high primary compaction and high secondary compaction, therefore described binding agent can be used for by directly pressing the preparation solid dosage forms.

The accompanying drawing summary

Fig. 1 illustrate to microcrystalline Cellulose (

The PH-105 grade) hot strength of sheet and the graph of a relation of primary compaction pressure under five kinds of different pressures.

Fig. 2 is right

The hot strength of PH-105 microcrystalline Cellulose sheet under different primary compaction pressure and the graph of a relation of secondary compaction pressure.

Fig. 3 is the sketch map of roll-in system, the continuous processing that this system provides tablet formulations to granulate.

Fig. 4 is the sheet hot strength that the MCC/ mannitol mixture with 75: 25 of coprocessing is handled under different primary compaction pressure and the graph of a relation of secondary compaction pressure.

Fig. 5 is to the dried blend of MCC/ mannitol (promptly not carrying out the physical mixture of coprocessing) the sheet hot strength under different primary compaction pressure and the graph of a relation of secondary compaction pressure with 75: 25.

Detailed Description Of The Invention

Unless point out in addition in the context, in specification and claims, term active component, excipient, sugar Pure and mild similar term also comprises the mixture of these materials. Unless otherwise prescribed, all percentages all are weight percent Number, temperature all is degree centigrade (Celsius temperature). But compacting/briquettability represents powder densified ability under pressure, and Term presses/and compactability represents to produce by compacting the ability of particle or tablet with special properties. Microcrystalline cellulose Material and the material that contains MCC refer to the material at least about 40 % by weight microcrystalline celluloses. This material can comprise greater than 40 % by weight microcrystalline celluloses, for example, at least about 50 % by weight microcrystalline celluloses, at least about 60 % by weight crystallite fibres Dimension is plain, at least about 65 % by weight microcrystalline celluloses, at least about 70 % by weight microcrystalline celluloses with at least about 75 weight The % microcrystalline cellulose.

Dry granulation

Solid dosage forms comprises material, one or more active components and optional one or more of the MCC of containing of the present invention Pharmaceutically acceptable excipient and/or lubricant. Use dry granulation to prepare two compaction step of solid dosage forms needs. First step is during roll-in or tablet are prefabricated, presses in the batching that will contain granulation binders and carries out when forming particle. Second step is during forming solid dosage forms or film-making, presses at the tablet formulations that will contain particle and carries out when in blocks.

Disclose this area, and microcrystalline cellulose shows the compactability that reduces after repeatedly pressing. After pressing for the first time The porosity of microcrystalline cellulose descends, and with respect to for the first time or the compacted microcrystalline cellulose before the primary compaction little The plain compactability that reduces of crystal fiber is relevant. Although be not subjected to the restriction of any theory or explanation, think in primary compaction Form during this time many hydrogen bonds, reduce the quantity in the possible hydrogen bond site that is used for secondary or presses subsequently.

But, have been found that when the material that contains microcrystalline Cellulose carried out primary compaction, the hot strength of gained material increased with compaction pressure, but be issued to limit value or steady level in higher compaction pressures.This can be known by Fig. 1, Fig. 1 illustrate by

The PH-105 microcrystalline Cellulose presses the hot strength of the ribbon of formation under the different primary compaction forces of five kinds (6.3kN, 13kN, 24kN, 33kN and 46kN).These primary compaction forces correspond respectively to about 50MPa, about 100MPa, about 185MPa, the primary compaction pressure of about 250MPa and about 350MPa.When being about 200MPa, primary compaction pressure reaches steady level.After applying elevated pressures, hot strength does not obviously increase, even reduces slightly.

Fig. 2 is illustrated in the hot strength of sheet of primary compaction pressure scope dry granulation and the graph of a relation of secondary compaction power.Be 4kN, 9kN, 14kN, the secondary compaction power of 19kN and 27kN corresponds respectively to about 50MPa, about 115MPa, about 180MPa, the secondary compaction pressure of about 240MPa and about 350MPa.The primary compaction pressure of each curve is shown in the little frame on this curve right side." 0MPa " curve display material is not pressed (that is, directly compacting, primary compaction only) again, is equivalent to the secondary compaction of primary compaction forces when being 0MPa.All the other curves are that the material that presses under the primary compaction pressure level that marks earlier obtains through pressing again.These primary compaction pressure are corresponding to the primary compaction forces shown in Fig. 1.Can see that secondary compaction (" compactability again ") descends gradually, this depends on the pressure that is used for primary compaction.Increase primary compaction pressure and cause " overcompaction ", the hot strength of secondary compaction is descended.

For be used for by roll-in then tabletting form tablet, the secondary compaction tensile strength of material after the secondary compaction of primary compaction that experiences 250MPa and 250MPa that contains MCC should be at least 5.5MPa, preferred 6.0MPa, that is, to having carried out the Materials Measurement secondary compaction tensile strength that contains MCC of primary compaction under near elementary hot strength or pressure in the meadow of elementary hot strength.

An aspect, described compositions elementary hot strength after the 250MPa primary compaction is at least 9.5MPa, and tensile strength is at least 5.5MPa after 250MPa primary compaction and 250MPa secondary compaction.In yet another aspect, the elementary hot strength of described compositions after the 250MPa primary compaction is at least 9.5MPa, and the maximum secondary hot strength is at least 6.0MPa after 250MPa primary compaction pressure and secondary compaction.The normally secondary compaction by the about 350MPa acquisition of ultimate tensile strength after the secondary compaction.

When carrying out coprocessing when microcrystalline Cellulose and sugar alcohol or with carboxymethyl cellulose, the elementary hot strength of compositions after the 250MPa primary compaction is at least 9.0MPa, and the tensile strength after 250MPa primary compaction pressure and 250MPa secondary compaction is at least 5.0MPa.In yet another aspect, when carrying out coprocessing when microcrystalline Cellulose and sugar alcohol or with carboxymethyl cellulose, the maximum secondary hot strength of compositions after 250MPa primary compaction pressure and secondary compaction is at least 6.5MPa.

Show some materials and can satisfy this standard.The mixture of the coprocessing of sugar alcohol and MCC satisfies this standard as the mixture of describing below.The MCC of coprocessing for example: the hot strength of the primary compaction of mannitol (85: 15) is 10.0MPa, and the tensile strength maximum of secondary compaction is 6.2MPa.The MCC of coprocessing: the hot strength of the primary compaction of mannitol (75: 25) is 9.5MPa, and the tensile strength maximum of secondary compaction is 5.5MPa.The MCC of coprocessing: the hot strength of the primary compaction of mannitol (95: 5) is 10.0MPa, and the tensile strength maximum of secondary compaction is 5.5MPa.The hot strength of the primary compaction of the MCC/ carboxymethyl cellulose (CMC) of coprocessing is 10.0MPa, and the tensile strength maximum of secondary compaction is 5.5MPa.

Though it is more bigger than the general required hot strength of tablet (being about 2MPa usually) to be at least the secondary compaction tensile strength of 5.5MPa, the tensile strength that these numeric representations are measured the tabletting that contains the MCC material that only contains not preparation, rather than be formulated in the tensile strength that contains the MCC material in the tablet.Should expect will some reduction with these hot strengths that contains the sheet of MCC material and the preparation of other components.

Roll-in

Roll-in (this area is also referred to as " roll compaction ") is that dried pressing/granulating forms the method for tablet, adopts the roll-in method when tablet formulations does not have essential flow behavior of formation sheet or sufficiently high bulk density.Roll squeezer utilizes pressure that tablet formulations is pressed and densification, and powder-stuck is become granule.The active component of processing by roll-in for example comprises, acetylsalicylic acid (aspirin), acetaminophen, amoxicillin, ibuprofen, penicillin, ranitidine and streptomycin.

Granulation is a kind of technology that size is enlarged, and wherein granule being flocked together becomes bigger aggregation, but still can identify the primary particles in the aggregation.Mixed uniformly powder (granulated formulations) is pushed the ribbon that forms compacted material between the reverse rotation roller, this ribbon is ground be granule then.The sketch map of roll squeezer shown in Fig. 3.Roll squeezer comprises roll assembly, pressing structure, hydraulic system and feed system.Before feed system is located immediately at roller, and determined granulated formulations to add the flow velocity of roller.Feed system can comprise one or more feed worms, and described screw rod forces granulated formulations to enter between the calender roller.Granulated formulations between two calender rollers by the time pressed.Granulated formulations from the maximum pressure zone by the time its volume reduce, form compacted solid material, be called sheet or ribbon.Compaction pressure is provided by hydraulic system, can regulate this system's body and produce required compaction pressure.Hydraulic system acts on one of them roller.As shown in Figure 3, rolling process be one press continuously, grind, sieve and incite somebody to action too bulky grain (" tailover ") and too granule (" particulate ") recirculation return the process of this technology.

This area that is configured as of various rollers all knows, for example by A.M.Falzone, and Ph.D.Thesis, release university (Purdue University) from sufferings, 1990 (U.M.I. of Michigan, United States Ann Arbor, job number 9313940 (U.M.I., Ann Arbor, MI, Order Number 9313940) describe.Rolling equipment can be purchased, as taking from the Illinois, America Elmhirst that Patrick company (Fitzpatrick Company, Elmhurst IL USA) now buys

Roll squeezer.This equipment takes among " the Introduction to Roll Compaction and the FitzpatrickCHILSONATOR " that Patrick company (FitzpatrickCompany Europe) publishes now in Europe to be described.

Tabletting

Tabletting is that the technical staff in tablet formation field all knows.Can exert pressure by the tablet formulations in tablet machine for described and form.Tablet machine comprises and is assemblied in the low punch the punch die from the bottom and has respective shapes and the upper punch of size that upper punch enters die cavity from the top after tablet formulations is filled die cavity.Tablet formulations in punch die is exerted pressure and is formed sheet by low punch and upper punch.The ability that tablet formulations flows freely into punch die to guarantee tablet formulations from hopper continuous-flow to punch die, it is very important evenly to fill punch die.Usually, add as the lubricant of magnesium stearate presses rear panel with promotion and discharges from punch die, and avoid being bonded on the punch face.

The tabletting process is at pharmacy textbook such as AGENNARO, Remington:The Science and Practice ofPharmacy, the 20th edition., Lippincott Williams﹠amp; Wilkins, Baltimore, MD describes in detail in 2000.

Microcrystalline Cellulose

Microcrystalline Cellulose (MCC) is the cellulose of purified part depolymerization, can obtain by the hydrolysis of various cellulose source, described cellulose source is just like timber, and wood pulp is as the sulfate and the sulfate pulp of bleaching, Cotton Gossypii, Caulis et Folium Lini, Fructus Cannabis, bast or leaves fiber, regenerated fiber prime form, soybean peel, shuck or shuck.Microcrystalline Cellulose is a white, odorlessness, and no taste can free-pouring relatively powder, water insoluble, organic solvent, diluted alkaline and diluted acid.

Hydrolysis can be by any realization in several known methods.Usually, with the preferred hydrochloric acid of mineral acid the preferred alpha-cellulose of the cellulose source source from the pulp form of fibre plant is handled.The little orderly zone of acid selective destruction cellulosic polymer chain, so stay the crystal region of more formation microcrystalline Cellulose.Then MCC is separated with reactant mixture, clean and remove by-product.The wet piece that forms contains 40-60 weight % moisture usually, and wet piece is represented with several titles, comprising: hydrocellulose, microcrystalline Cellulose, the wet cake of microcrystalline Cellulose or the wet cake of abbreviation.Preparation of microcrystalline cellulose discloses in the United States Patent (USP) of Battista the 2nd, 978, No. 446 and the 3rd, 146, No. 168.

Microcrystalline Cellulose can (Edward Mendell Co. be Inc.) with trade name from Edward Mendle Ltd.

Buy and from FMC Corp. with

Buy.Can obtain the microcrystalline Cellulose of the different several grades of granularity, density and moisture, for example,

PH-I01, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-301 and PH-302.

The compositions of coprocessing

The compositions of coprocessing comprises two kinds of components, MCC and sugar alcohol.Two kinds of components are with microcrystalline Cellulose: sugar alcohol is about 99: 1 to 1: 99 weight ratio and exists.When MCC and sugar alcohol such as mannitol coprocessing, these two kinds of component MCC: the weight ratio of sugar alcohol preferably is about 70: 30 to 95: 5, more preferably 75: 25 to 90: 10.

Sugar alcohol refers to polyalcohols, comprises acyclic or alicyclic polyhydric alcohol.Acyclic sugar alcohols has general formula C _nH _N+2(OH) _nConventional sugar alcohol for example comprises mannitol, Pyrusussuriensis (sugar) alcohol, xylitol, lactose, hydroxyl isomaltulose (isomalt).Maltose alcohol, erythritol and threitol.Preferred sugar alcohol is to contain 4-6 carbon atom (that is, n is 4-6), especially those sugar alcohols of 5 or 6 carbon atoms (n is 5 or 6).

Particularly preferred sugar alcohol is mannitol [(C ₆H ₈(OH) ₆)] [(2R, 3R, 4R, 5R)-1,2,3,4,5, the 6-hexanhexol] [CAS#69-65-8].Mannitol is non-hygroscopic, produces to have low viscous relatively solution, and has relative high melt point (about 167-170 ℃).These character make the water slurry of microcrystalline cellulose/mannitol can carry out spray drying easily, produce the microcrystalline cellulose/mannitol of coprocessing.

The compositions of coprocessing is a particulate composition, and its particle mean size is about the 25-1000 micron.Particle mean size is about the 50-200 micron usually, and more preferably from about the 70-120 micron is more preferably the 80-110 micron, for example about 90 microns.The loose bulk density of co-processed product (LBD) is less than or equal to 0.60 gram per centimeter usually ³Be 70: 30 to 95: 5 microcrystalline Cellulose to ratio of component: the loose bulk density of the co-processed product of mannitol is about the 0.35-0.50 gram per centimeter usually ³Its pH is about 3.0-8.5, preferably is about neutrality.When using carboxymethyl cellulose, compositions can comprise at least 80 weight %MCC, at least 85 weight %MCC, at least 90 weight %, or at least 95 weight %MCC.

The microcrystalline Cellulose of coprocessing: the preparation of sugar alcohol composite and property description are acted on behalf of case numbering 60560-USA at the common U.S. Patent application FMC that submits to, in " microcrystalline Cellulose of coprocessing and sugar alcohol are as the excipient (Co-processed Microcrystalline Cellulose and Sugar Alcohol as anExcipient for Tablet Formulations) of tablet formulations ", this application is incorporated into this by reference.

Coprocessing

The method for compositions of preparation coprocessing comprises for example water slurry of mannitol of the MCC that forms fine dispersion and sugar alcohol.Regulate the relative quantity of two kinds of components in the slurry, to reach required specified weight ratio in final dried co-processed product.Then, anhydrate the water slurry drying, form the product of coprocessing by removing.Preferably, the described slurry spray drying technology that adopts this area all to know carries out drying.But also can adopt other dry technologies, as expansion drying, ring drying, dish is dry, vacuum drying, dielectric drying and microwave drying.

The wet cake that the preferably conventional MCC manufacturing process of MCC produces.Wet cake is the also not dry MCC that becomes the conventional MCC of free flowing powder.Perhaps, exsiccant MCC can the rehydrated water slurry that produces MCC.The granularity that is used for the MCC of water slurry is a regular particle size, the granularity in the promptly conventional MCC preparation.

Can adopt in the several method any to prepare the water slurry of these two components.Sugar alcohol can join in the microcrystalline Cellulose slurry in water with solid or predissolve.Usually solid concentration is about 5-25 weight % microcrystalline Cellulose, preferably about 10-20 weight % microcrystalline Cellulose.The sugar alcohol that adds definitely measure certainly in slurry MCC content and at the ratio of two kinds of required components of co-processed product.Can also add entry when needing rarer slurry.With total slurry weight is benchmark, and the total solid content of water slurry is at least 10 weight % preferably,, more preferably at least 20 weight % solids.Higher solids content is desirable, because can suitably reduce the water yield that must remove in the drying steps like this.The upper limit of solid content is determined by the operational constraints of the drying equipment that uses usually in the water slurry.When adopting preferred drying process with atomizing, the solid content of 20-30 weight % is the representative solid content of easy-to-handle water slurry.Can adopt about 10-80 ℃ the environment or the slurry temperature of rising, higher slurry temperature is that the drying equipment of some type is desirable.

The drying of the water slurry of fine dispersion preferably realizes by spray drying.Can use conventional spray drying device.The rule of operation that spray drying those skilled in the art are familiar with can be applicable to the spray drying step of this method.Usually adopt the outlet temperature of exsiccator to control the residual moisture content that reaches in the compositions of coprocessing.According to dry type and dry amount, the concentration of MCC and sugar alcohol in the slurry, the product of coprocessing will have different granularities, density, pH and moisture.Because this reason, the drying steps of coprocessing process is even more important, so spray drying is preferred drying means.

The loose bulk density of the co-processed composition that the spray drying slurry produces is less than or equal to 0.60 gram per centimeter ³, preferred 0.20-0.60 gram per centimeter ³Compare with the dried blend of material or corresponding wet granular, the compositions that spray drying produces has preferred compactability and preferred compactability again under the lubricant existence condition.Loose bulk density can be less than 0.55 gram per centimeter ³, less than 0.50 gram per centimeter ³, less than 0.45 gram per centimeter ³, less than 0.40 gram per centimeter ³, less than 0.35 gram per centimeter ³, less than 0.30 gram per centimeter ³, less than 0.25 gram per centimeter ³The product of the coprocessing that drying process is reclaimed is the free flowing granule solid.The granularity of product becomes with the spray dryer setting, can regulate during feed rate and the spray drying speed of nebulizer dish by those skilled in the art and control.

Solid dosage forms

Solid dosage forms comprises material, one or more active components and one or more optional pharmaceutically acceptable excipient of the MCC of containing of the present invention.According to the conventional pharmaceutical hybrid technology, the conventional tablet batching can be by preparing one or more active components and at least a mixed with excipients.Directly press preparation solid dosage forms or tablet for adopting, tablet formulations must have required physical characteristic.Wherein, tablet formulations must can free-flow, must be lubricated, and importantly must have enough compactability and keep harmless pressing the back, and enough solid subsequently the operational example of being used for applies and packing as handling to guarantee solid dosage forms.

By the formation sheet of exerting pressure to the tablet formulations on tablet machine.Tablet machine comprises and is assemblied in the low punch the punch die from the bottom and has respective shapes and the upper punch of size that upper punch enters die cavity from the top after tablet formulations is filled die cavity.By being applied on low punch and the upper punch, pressure forms sheet.The ability that tablet formulations flows freely into punch die is to guaranteeing evenly to fill punch die and material is very important from the tablet formulations source continuous-flow of for example loading hopper.The lubricity of tablet formulations is a deciding factor to the preparation solid dosage forms, because the material of compacting must be able to easily break away from from punch face.Sheet also must be able to be discharged from punch die after compacting neatly.

Because active component does not always have these character, therefore developed the tablet formulation method to give tablet formulations with these desirable characteristics.Usually tablet formulations comprises one or more additives or excipient, and these additives or excipient are given tablet formulations required free-flow, lubricity and bond property.

The excipient that is used for dry granulate formulations should have good compactability again and dilution probability, makes it possible to granule is pressed in flakes.Excipient should not quicken the chemistry and/or the physical decomposition of active component, should not influence the bioavailability of active component.Excipient should be that the physiology is inert, and should not have the dissolving that destination influences disintegration of tablet or active component.Excipient should show low lubricant sensitivity, and guarantees the uniformity of acceptable activity constituent content.Conventional excipients is selected from down group: disintegrating agent, fluidizer, filler, diluent, coloring agent, flavorant, stabilizing agent and lubricant.The selection of excipient and the composition of tablet formulations depend on active component and the amount of active ingredients in the batching, tablet type, the characteristic that tablet formulations and the sheet made are required, and the preparation method that adopts.These tablets comprise rapid release, and medicine dissolved in very short time for this reason, discharge at once and improve the tablet that discharges, and it comprises that great majority swallow oral tablet.

The acceptable excipient of pharmacy is known for those skilled in the art, for example discloses in No. the 6th, 936,628, the United States Patent (USP) of No. the 6th, 936,277, the United States Patent (USP) of Staniforth and Lee.Add MCC to improve the compactability of tablet.Add excipient such as diluent, binding agent, fluidizer and lubricant make the tabletting operation more effective as processing aid.The excipient of other types can improve or reduce the disintegration rate of tablet, improves the taste (for example, sweeting agent) of tablet, perhaps gives tablet color or fragrance.

Usually adding lubricant is sticking on the drift during the film-making to prevent batching.Lubricant commonly used comprises magnesium stearate and calcium stearate.Lubricant accounts for about 0.5-3.0 weight % of batching usually.Antitack agent prevents that tablet formulations from sticking on punch face and the die wall.Antitack agent and magnesium stearate are used in combination when having sticking problem.Antitack agent commonly used is corn starch and Talcum.Often add diluent, filler or extender to increase the bulk weight of the material of wanting film-making, so that tablet has practical dimensions.This mode usually is essential in the less relatively situation of the dosage of active component.Conventional filler comprises lactose, calcium hydrogen phosphate, calcium carbonate, efflorescence cellulose, dextrates (dextrates), mannitol, starch, pregelatinized Starch, and their mixture, sugar alcohol such as Pyrusussuriensis (sugar) alcohol, mannitol and xylitol also are used as filler, especially in masticable tablet formulations.The most significant difference is hygroscopicity and dissolubility between the pure and mild mannitol of Pyrusussuriensis (sugar).Pyrusussuriensis (sugar) alcohol is moisture absorption greater than 65% relative humidity the time, and mannitol is non-moisture absorption.The water-soluble of Pyrusussuriensis (sugar) alcohol is greater than mannitol.

Adding binding agent makes powdered material have adhesiveness.Typical binders comprises starch, microcrystalline Cellulose and saccharide, and as sucrose, glucose, dextrose and lactose.Stabilizing agent reduces the decomposition rate of active component.Conventional stabilizing agent is antioxidant such as ascorbic acid.

The normal disintegrating agent that adds is to guarantee that tablet has acceptable rate of dissolution in environment for use (as at gastrointestinal tract).Disintegrating agent becomes sheet the microgranule of active component and excipient with particle spliting.Though MCC and partially pregelatinized starch implement to press the function with disintegrate through being usually used in preparing burden, often need additive superdisintegrant (super-disintegrant) as cross-linking sodium carboxymethyl cellulose, primojel or crospovidone.In tablet formulations, use fluidizer mobile to improve.They are more through being usually used in dried blend rather than wet granulated formulations.Because flowing when coating of particles and size, fluidizer have been improved low concentration.They are blended in the final tablet formulations with the form of doing.The most frequently used fluidizer is an alkali metal stearic acid salt, colloidal silica (

) and Talcum.

Can make tablet have required characteristic by coloring agent (that is, dyestuff and pigment), natural or artificial sweetening agent and flavorant.Can also there be wetting agent, be also referred to as surfactant.Tablet can also coating.

The value of circular tablet is about the 50-500 milligram usually, and Caplet is about the 200-1200 milligram.But can suitably be shaped according to other batchings of the present invention preparation is used for other purposes or position, and other body cavitys for example are as periodontal pocket (periodontal pocket), surgical wound and vagina.To special-purpose, as chewable tablets, antacid tablet, tablet,vaginal and implant, tablet can be bigger.

Compositions also is suitable for

The prepared solid dosage forms.Right

The solid dosage forms of technology can be pressed formation powder compacts gently to tablet formulations or granulated formulations, with film the powder compacts is carried out coating (enrobing).The method and apparatus of solid dosage forms that is used to form coating is at WO 03/096963, WO2005/030115, and WO 2005/030116, discloses among WO 2005/030379 and the WO 2006/032828, and the content that these patents disclosed is by with reference to being incorporated into this.

Commercial Application

The MCC of containing material of the present invention can be used as the binding agent in the solid dosage forms of tablet, and solid dosage forms comprises one or more active components and one or more optional other excipient.Containing the MCC material especially can be as passing through the directly binding agent of the batching of compacting preparation.The MCC material is mainly used in medicine and veterinary drug is used though contain, and can be used for other field, for example, and agricultural, food, cosmetics and other commercial Application.

Can observe beneficial property of the present invention referring to following examples, the present invention will be described but be not construed as limiting the invention for embodiment.

Embodiment

Nomenclature

Conventional method

Following method commonly used is measured elementary hot strength and tensile strength.Each loose test material is pressed the preparation compacts under five kinds of different compaction pressure.On special-purpose Pneumatic hydraulic pelleter " FlexiTab ", press as the roll-in simulator.Compacts is circular flat piece (13 millimeters, 750 milligrams).Measure the crushing strength of each compacts, and tensile strength calculated.Compacts is ground granule into narrow particle size distribution (＜1 millimeter).

For measuring compactability again, with above-mentioned make five kinds particulate each under five kinds of different compaction pressure, press, prepare circular flat piece (10 millimeters, 500 milligrams).Measure the crushing strength of every kind of sheet, and tensile strength calculated.

Embodiment 1

Present embodiment shows that the highest secondary compaction tensile strength of MCC/ sugar alcohol mixtures of coprocessing is greater than the hot strength of same component, ejusdem generis physical mixture.

75: 25 MCC/ mannitol mixture of coprocessing makes by mannitol being added the wet cake of MCC and slurry being carried out spray drying.75: 25 MCC/ mannitol mixture of coprocessing and 75: 25 not the MCC/ mannitol physical mixture of coprocessing are tested according to described conventional method separately.The Fig. 4 that the results are shown in to the mixture of coprocessing.Test result to physical mixture is shown in Fig. 5.

The MCC of coprocessing: the maximum primary compaction tensile strength of mannitol is 9.5MPa.Maximum secondary compaction tensile strength is 6.5MPa., the maximum primary compaction tensile strength of the physical mixture of MCC and mannitol is 9.0MPa, and maximum secondary compaction tensile strength is 5.0MPa.

Embodiment 2

The MCC of coprocessing: CMC by the following method, by 4%

7HF product level sodium carboxymethylcellulose (as, per 100 gram MCC add 4 gram CMC) preparation, this method does not apply shear conditions to MCC.The wet cake of MCC is dispersed in preparation 15% slurry in the deionized water.This slurry is heated to 60 ℃, regulates slurry pH to 8 with ammonia.In slurry, add enough calcium chloride and make its concentration reach 0.01 mol, use then

Blender stirred 5 minutes.In this mixture, add efflorescence CMC, abundant dispersed with stirring CMC simultaneously, then under treatment conditions with this batch of material spray drying, obtain with

The granularity that PH-101 is suitable.

Embodiment 3

Various materials adopt conventional method to test.Various materials after the 250MPa primary compaction primary compaction tensile strength (elementary hot strength) and list in table 1 at the ultimate tensile strength (tensile strength) of secondary compaction, also be listed in the value of the material of preparation in embodiment 1 and 2 and/or test in the table 1.

Table 1

^aAfter the 250MPa primary compaction.

^bAfter 250MPa primary compaction and the 250MPa secondary compaction.

^cUltimate tensile strength is after 250MPa primary compaction and about 350MPa secondary compaction.

After describing the present invention, we require following and rights and interests its equivalents.

Claims (17)

1. compositions, said composition comprises at least 60 weight % and contains the microcrystalline cellulose cellulosic material; The elementary hot strength of described compositions after the 250MPa primary compaction is at least 9.5MPa; Be at least 5.5MPa in 250MPa primary compaction and the tensile strength after the 250MPa secondary compaction.

2. compositions as claimed in claim 1, it is characterized in that, the described material that contains microcrystalline Cellulose is and the microcrystalline Cellulose of at least a sugar alcohol coprocessing, and the ratio of microcrystalline Cellulose and at least a sugar alcohol is about 70: 30 to 95: 5, and described at least a sugar alcohol has four carbon atom at least.

3. compositions, said composition comprises at least 60 weight % and contains the microcrystalline cellulose cellulosic material; The described material that contains microcrystalline Cellulose is the microcrystalline Cellulose with the material coprocessing that is selected from sugar alcohol or carboxymethyl cellulose; The elementary hot strength of described compositions after the 250MPa primary compaction is at least 9.0MPa; Be at least 5.0MPa in 250MPa primary compaction and the tensile strength after the 250MPa secondary compaction.

4. compositions as claimed in claim 3, it is characterized in that, the described material that contains microcrystalline Cellulose is and the microcrystalline Cellulose of at least a sugar alcohol coprocessing, and the ratio of microcrystalline Cellulose and at least a sugar alcohol is about 70: 30 to 95: 5, and described at least a sugar alcohol has four carbon atom at least.

5. as each described compositions among the claim 1-4, it is characterized in that described at least a sugar alcohol is a mannitol.

6. as claim 1 or 3 described compositionss, it is characterized in that the described material that contains microcrystalline Cellulose is the microcrystalline Cellulose with the carboxymethyl cellulose coprocessing.

7. compositions, said composition comprises at least 60 weight % and contains the microcrystalline cellulose cellulosic material; Described compositions behind 250MPa primary compaction and secondary compression the maximum secondary hot strength be at least 6.5MPa.

8. as each described compositions among the claim 1-7, it is characterized in that described compositions comprises the material that contains microcrystalline Cellulose of at least 65 weight %.

9. a granulated formulations comprises each described compositions and at least a active component among the claim 1-8.

10. granulated formulations as claimed in claim 9, described granulated formulations also comprise at least a lubricant of 0.5-3.0%.

11. one kind forms particulate method, this method may further comprise the steps:

Exert pressure to form compacts to claim 9 or 10 described granulated formulations, this compacts is ground the formation granule.

12. a granule forms by the described method of claim 11.

13. a method that forms solid dosage forms, this method comprise the described granule of claim 12 is pressed the step that forms solid dosage forms.

14. a solid dosage forms adopts the described method preparation of claim 13.

15. solid dosage forms as claimed in claim 14 is characterized in that, the hardness of described solid dosage forms is at least 2MPa.

16. a method of testing binding agent, described binding agent comprise at least about 40 weight % and contain the microcrystalline cellulose cellulosic material; Said method comprising the steps of:

1) binding agent is pressed under 250Pa, and measure elementary hot strength;

2) or with the binding agent that forms in the step 1) under 250Pa, press, measure tensile strength; With

3) select binding agent, elementary hot strength feasible or (1) binding agent is at least 9.5MPa, and tensile strength is at least 6MPa; Or the material that (2) contain microcrystalline Cellulose is and the microcrystalline Cellulose of the material coprocessing that is selected from sugar alcohol or carboxymethyl cellulose, and the maximum primary hot strength of described binding agent is at least 9.0MPa, and tensile strength is at least 5.0MPa.

17. method as claimed in claim 16 is characterized in that, described binding agent comprises at least about 65 weight % microcrystalline Cellulose.

Images