CN101316579A - Uniform films for rapid-dissolve dosage form incorporating anti-tacking compositions - Google Patents

Abstract

The present invention relates to water-soluble films incorporating anti-tacking agents and methods of their preparation. Anti-tacking agents may improve the flow characteristics of the compositions and thereby reduce the problem of film adhering to a user's mouth or to other units of film. In particular, the present invention relates to edible water-soluble delivery systems in the form of a film composition including a water-soluble polymer, an active component selected from cosmetic agents, pharmaceutical agents, vitamins, bioactive agents and combinations thereof and at least one anti-tacking agent.

Description

The uniform films that is used for rapid-dissolve dosage form that contains anti-tacking compositions

Invention field

The present invention relates to contain the rapidly dissolving film of antiplastering aid and their preparation method.Described film can also contain the active component that is evenly distributed in the film.

Related background art

Active component (as medicine or medicament) can be prepared into tablet form so that obtain accurate and uniform dosage.Yet the form of this preparation and distribution medicine has many shortcomings, comprising: must add a high proportion of adjuvant and just can reach manipulable dosage size, therefore bigger medicament forms needs extra storage area; And making up a prescription comprises when tablet counted and might bring inexactness.In addition, many people (estimation accounts for total population 28% more than) have any problem aspect swallow tablet.Although in order to overcome dysphagia, can make tablet rupture Cheng Gengxiao fragment or even it can be pulverized, for many tablets or pill form, this is not suitable solution.For example, pulverize or destroy tablet or pill form and absorb and also can destroy the sustained release characteristic so that mixes separately or with food.

As tablet and pill or the choosing, also can use film to carry active component, as medicine, medicament etc.Yet the film in past and have many unfavorable characteristics with this method for preparing drug delivery system can not adopt them in practice.

The United States Patent (USP) the 4th, 136, No. 145 (" Fuchs ") of expiration of time limit that is combined with people such as the film of active constituents of medicine such as Fuchs is described.These films can be made sheet, and drying cuts into each dosage then.The Fuchs open source literature has proposed to prepare the method for uniform films, comprises water-soluble polymer, surfactant, flavoring agent, sweeting agent, plasticizer and drug regimen.Disclosed that the softish film that these can be mentioned is used for oral, part or intestinal is used.The example of the concrete purposes that Fuchs discloses comprises the membranous part that film is used for health, comprises oral cavity, rectum, vagina, nose and ear.

Yet, according to the Fuchs disclosed method film is detected, find that particle aggregation or reunion can take place this class film, i.e. self aggregation, making them is uneven in essence.This possibility of result is that the method parameter by Fuchs causes, although not open, this method may comprise and adopts long drying time, reunites thereby impel intramolecularly captivation, convection current power, air-flow etc. to form this classes.

The formation of reuniting makes any activating agent of membrane component and existence be random distribution.When relating to heavy dose, the minor alteration of film size aspect all can cause the greatest differences of activating agent quantity in the every film.If comprise the low dosage activating agent in this class film, then some position of possible film is basically without any activating agent.Owing to diaphragm will be cut into unit dose usually, so some dosage may lack the activating agent of treatment suggestion or the quantity not sufficient of activating agent.It is deleterious to the patient that the cutting film can't obtain highly accurate active dose.For this reason, the dosage that forms as the processing method of Fuchs can not satisfy the strict standard of government or administrative organization such as the United States Federal's FAD (" FDA ") because the difference of active dose in its dosage form.At present, each worldwide administrative authority all requires the difference of the active dose that exists in the dosage form not surpass 10%.When being used for film base type, in fact be exactly to require to be present in the film equably.

Proposed to cause film uneven in the United States Patent (USP) of Schmidt the 4th, 849, No. 246 (" Schmidt ") from agglomeration traits.Schmidt spells out the Fuchs disclosed method can not provide uniform films, and recognizes that the generation of non-homogeneous film has hindered the accurate quantification that is even more important at pharmaceutical field as mentioned above.Schmidt has abandoned providing as monofilm as described in the Fuchs idea of accurate dosage form, replaces to attempt addressing this problem by forming multilayer film.And his method is the rapid process of the multistep of increase expense and complexity, does not have feasibility in the commerce utilization.

Other United States Patent (USP) has directly proposed the inherent granule of conventional film technique from reuniting and non-homogeneous problem.In once overcoming trial heterogeneous, the United States Patent (USP) 5,629 of Horstmann etc., 003 and the United States Patent (USP) 5,948,430 of Zerbe etc. in added other composition, promptly be respectively into gel and polyhydric alcohol, before dry, increase film viscosity to make great efforts to alleviate the gathering of component in the film.The shortcoming of these methods is to need other component, and this will change extra-pay and manufacturing step into.And these two kinds of methods have all been utilized conventional time-consuming drying means, bathe as the high temperature air that uses drying oven, drying tunnel, vacuum desiccator or other this class drying equipment.Although used viscous modifier, long-time drying still can impel activating agent and other adjuvant to assemble.This class course of processing is also being emitted and is being made activating agent (be medicine, or vitamin C, or other component) Long contact time moisture and high temperature and its was lost efficacy or even deleterious risk.

Activating agent can be degraded during worrying long-term contact wetting, itself can not provide uniform films the conventional drying method.Thermo-contact time span during the conventional processing is often referred to " heat history (heat history) ", carries out the heat treated mode of this class the formation and the form thereof of gained film product had a direct impact.The conventional drying method that is fit to very much the thicker relatively film of bound drug activating agent via needs especially is difficult to reach uniformity.Because when dry, the film surface does not experience identical external condition simultaneously with film inside, therefore the thicker uniform films of more difficult acquisition.Therefore, the observation of the thicker film that the conventional processing method of this class is made shows the heterogeneous texture that convection current and intramolecular force produce, and is higher than 10% moisture in order to keep flexible needs.Free water component interference medicament for a long time brings potential problems, thereby final products can not be kept consistently.

The conventional drying method generally includes the forced hot air that utilization is produced by drying oven, drying tunnel etc.The difficulty that obtains uniform films is directly relevant with the water evaporation process in the rheological equationm of state and the film-forming composition.When aqueous solutions of polymers surface contacted with high temperature gas flow, during by air stove, superficial water evaporated at once and forms polymeric film or skin from the teeth outwards as film-forming composition.Sealed surperficial following remaining aqueous film-forming composition like this, formed barrier one, remaining water must oneself be made great efforts to penetrate this road film and could be evaporated, to obtain exsiccant film.Along with the lasting rising of the outer temperature of film, the following water vapor pressure in film surface increases, and the stretched film surface is finally torn the film surface and made the water vapour loss.In case after the water vapour loss, described polymer film surface can form again, repeats this process, up to the film bone dry.Observe the result who constantly destroys and form again in the film surface and produce uneven and " chain reaction " of uneven film thus.Usually, according to different polymer, the surface makes remaining shipwreck to discharge deadend, causes very long drying time, higher temperature and power consumption more.

Other factors as hybrid technology, also plays effect in manufacturing is suitable for the pharmaceutical film of commercialization and management board approval.Air may be entrained in the compositions between mixing period or during the system film afterwards, when the drying stage water evaporates, may in the film product, reserve a little spaces like this.Near the described space film usually can destroy, and causes the film air spots smooth and cause telolemma product inhomogeneous thus.Even in the described film that bubble causes do not break in the space, uniformity still can be influenced.Because the space of described non-uniform Distribution is to be occupied the zone by what film composition occupied under other situation, so this situation also provides non-homogeneous film.None mentions above-mentioned patent or proposes to solve by the scheme that air threw into question that enters film.

And preceding in first packing (as medicinal cupping) and secondary package (as medicated bag or blister package), film will experience many procedure of processings earlier.Described procedure of processing is great challenge for the high-quality film that exploitation has best film surface characteristic such as low-friction coefficient or high sliding rate.The main points of whole process are at the integrity of keeping film during begin to be fabricated onto final packaging.Therefore, need prevent or alleviate the problem that diminishes film integrality that as after after a while, film softens, is clamminess, adheres to, becomes dry or becomes fragile.

Say that more specifically OTC (over-the-counter) film product as sugar-coat and respiratory membrane, is packaged in the medicinal cupping that contains 16 film units (also being called lath) or more a plurality of film unit (every jar reaches 24 or even 32 lamina membranacea bars).Every jar lamina membranacea bar quantity changes according to factors such as product type, active dose and packing configurations.Yet, when at a plurality of template bar of jar intermediate package, the inter-adhesive problem of lath usually can appear.

Adhesion is the problem that the edible film product usually can run between the lamina membranacea bar, may be caused by a variety of causes.For example, under the certain situation, adhesion may be to be caused by the component that adopts in the film manufacturing between the template bar.Component such as flavoring agent, plasticizer and activating agent sometimes can soften film and the quality of film is had adverse effect in the film.For example, in the film with high-load acidify agent, acid can produce extra plastication to film.The number acid in the film or the hygroscopicity of other component may be strengthened this class influence.

Under the certain situation, the adhesion between the lamina membranacea bar may be to change the film qualitative change that causes by temperature and/or humidity to cause.Some films can become sticky when non-optimum temperature of Long contact time and/or damp condition.This problem can be amplified in the very narrow product of best storage temperature and/or humidity range.

In general, show viscosity or may there be many problems in the film that can become sticky after a period of time.At first, when film has viscosity, will always roll up and change son volume into, and further change the lamina membranacea bar into and become more difficult in fact.In addition, when superposeing in packing as jar, the adhesive film lath can be bonded to each other.Therefore, user is difficult to once take out a lamina membranacea bar from the film packing.Generally speaking, this class adhesion in the packing has reduced the aesthetic property of lamina membranacea bar and the facility that individual consumer is used.

Therefore, the compositions that each film can be slided relative to one another, thereby provide be convenient to transform, storage stability is the highest and consumer is easy to benefits such as use.In addition, need the method for this class film of preparation, make component wherein keep uniform distribution, thereby prevent undesirable clustering phenomena and improve the uniformity of telolemma product.

Summary of the invention

One aspect of the present invention provides a kind of edible film that is used for active agent delivery, and described film comprises: the edible water-soluble polymer; At least a antiplastering aid that is selected from lubricant, antitack agent, fluidizer and combination thereof; With the active component that is selected from enamel, medicament, vitamin, bioactivator and combination thereof, described film can self-supporting.

The present invention provides a kind of edible film that is used for active agent delivery on the other hand, and described film comprises: the edible water-soluble polymers compositions that contains at least a polymer that is selected from hydroxypropyl cellulose, hydroxypropyl emthylcellulose, poly(ethylene oxide) and combination thereof; Be selected from the active component of enamel, medicament, vitamin, bioactivator and combination thereof; With contain the antiplastering aid that content accounts for the vitamin E TPGS of the heavy 0.01-20% of film.

The present invention provides a kind of edible film that is used for active agent delivery on the other hand, and described film comprises: contain poly(ethylene oxide) and the edible water-soluble polymers compositions that is selected from hydroxypropyl cellulose, hydroxypropyl emthylcellulose and combination of polymers thereof; Be enough to provide vitamin E TPGS anti-stick and the treatment characteristic with content, described film can self-supporting.

In some embodiments, a kind of edible film that is used for active agent delivery is provided, described film comprises: the edible water-soluble polymer that contains poly(ethylene oxide), hydroxypropyl cellulose and dextrosan, wherein, poly(ethylene oxide): hydroxypropyl cellulose: the ratio of dextrosan is about 45: 45: 10; Be selected from the active component of enamel, medicament, vitamin, bioactivator and combination thereof; With at least a antiplastering aid.

On the other hand, provide a kind of edible film that is used for active agent delivery, described film comprises: (a) have at least one surperficial self-supporting film, described film comprises: (i) edible water-soluble polymer; (ii) be selected from the active component of enamel, medicament, vitamin, bioactivator and combination thereof; (b) be positioned at least one lip-deep covering of self-supporting film, described covering contains at least a antiplastering aid.

Some embodiments provide a kind of multilayer film that is used for active agent delivery, and described film comprises: (a) at least one first rete, and it contains: (i) edible water-soluble polymer and (ii) antiplastering aid; (b) second rete, the active component that it contains (i) edible water-soluble polymer and (ii) is selected from enamel, medicament, vitamin, bioactivator and combination thereof.Described first rete contacts basically with described second rete.

The present invention also provides the method for preparing the equally distributed basically self-supporting film of each component, may further comprise the steps: with the edible water-soluble polymer, solvent, the active component and at least a antiplastering aid that are selected from enamel, medicament, vitamin, bioactivator and combination thereof are combined to form the equally distributed substrate of each component; Form the self-supporting film by substrate; Surface with end face and bottom surface is provided; Described film is transported to the end face on described surface; With by the heating of the bottom surface on described surface is made the film drying.

Brief Description Of Drawings

Fig. 1 shows the side view of the packing that contains unit dose film of the present invention.

Fig. 2 shows two top views in abutting connection with packing that contain independent unit dosage forms of the present invention, separates by tearing perforation.

Fig. 3 shows the side view of Fig. 2 of stacking construction arrangement in abutting connection with packing.

Fig. 4 shows the perspective view of the allotter that distributes described encapsulation unit dosage forms, and allotter contains the encapsulation unit dosage forms of stacking construction.

Fig. 5 is the sketch map of the paired unit dose packaging of a volume of the present invention.

Fig. 6 is the sketch map that is suitable for being pre-mixed, adding activating agent and follows the film forming manufacturing equipment of shape.

Fig. 7 is the sketch map that is suitable for the equipment of dry film of the present invention.

Detailed Description Of The Invention

For purposes of the present invention; term " non-self aggregation is evenly heterogeneous " refers to the performance of film of the present invention; described film adds that by one or more components polar solvent forms, and can significantly reduce the phenomenon that component is assembled or reunited in the film that usually can experience when (namely almost or fully not occuring) forms film with the conventional drying method such as high temperature air bath, drying tunnel, vacuum desiccator or other this class drying equipment that adopts drying oven. The term " heterogeneity " that the present invention adopts comprises in conjunction with one-component such as polymer, and the film of the combination of each component such as polymer and activating agent. " evenly heterogeneous " comprises gathering or the reunion that usually can occur when basically not adopting conventional mixing and heated drying method to form film.

And the thickness of film of the present invention is basically consistent, and this also is that conventional drying method for drying water based polyalcohol system can not provide. Can't obtain consistent thickness the uniformity that component distributes in given diaphragm area is produced adverse effect.

By polymer and the polar solvent of suitable selection, or select the combination that also comprises a kind of active component and other fillers as known in the art to produce film product of the present invention. By adopting selected casting or deposition process and controllable dry drying method, it is evenly heterogeneous that the component in these films has non-self aggregation. The example of controllable dry drying method includes but not limited to: the United States Patent (USP) the 4th that uses Magoon, 631, disclosed equipment in No. 837 (" Magoon ") (it is for referencial use to include in full this paper in it), and the hot-air impingement flow is through bottom and bottom-heated dish. The another kind of dry technology that obtains film of the present invention is not have the not controlled radiant drying of controlled airflow, such as infrared ray and radio-frequency radiation (being microwave).

The purpose of described drying means provides the membrane drying process of avoided purposely causing complication (such as famous " ripples " effect), and it is relevant with the conventional drying method, and at first then the upper surface of desciccator diaphragm collects internal moisture. In the conventional oven drying means, when the moisture of internal gathering evaporated subsequently, end face was torn and changes, and then again formed. The present invention has avoided these complicated processes, by the bottom surface of first desciccator diaphragm or avoided the film end face to form polymer film (skin) before the desciccator diaphragm depths providing uniform films. This can realize in the following manner: to film bottom surface heating and the top there is no air-flow; Perhaps adopt control microwave to come evaporating film interior moisture or other polar solvent, same, the top there is no air-flow. Also or choosing, can flow to realize drying by adopting balanced fluid, the airflow balancing of uniform films is provided such as control bottom and top stream. In this case, point to the situation that power that the described air-flow at film top should not can cause air-flow to produce moves the particle that exists in the wet film. In addition, the air-flow that points to the film bottom is preferably controlled, thereby makes the film can the lifting because of the power of air-flow. Not controlled airflow above or below the film can cause inhomogeneous in telolemma product. The humidity level that can also suitably regulate the end face peripheral region prevents the too early closure of polymer surfaces or skinning.

This membrane drying process has a plurality of advantages. Comprising drying time and more uniform film are surperficial faster, and each component evenly distributes in any given area of film. In addition, faster drying time can be in film very fast generation viscosity, further support each component evenly to distribute and reduce the gathering of each component in the telolemma product. Ideally, the drying of film is at about 10 minutes or shorter or betterly carry out in about 5 minutes or shorter time.

When paying close attention to the cohesion that reduces each component of composition, the present invention can produce especially uniformly film product. Introduce and dispose excess air by avoiding in mixed process, selective polymer and solvent provide controlled viscosity, and by upwards film being carried out drying from the bottom fast, can obtain this class film.

Product of the present invention and method rely on each production stage of described film to cooperatively interact to provide the film of each component self aggregation in the remarkable minimizing film. Particularly, these steps comprise concrete film build method, prevent from carrying secretly composition mixture preparation method, the viscosity that is controlled to film composition and the membrane drying process that air inlet is steeped. More specifically, in order to prevent surfactant precipitate, when described activating agent was insoluble to selected polar solvent, component of mixture viscosity is higher then to be particularly useful. Yet viscosity can not be too high and hinder or hinder selected casting method, and described method should comprise the reverse roll coating, and this is because it can provide the basically film of consistency of thickness.

Except film viscosity or film-forming components or substrate, the present invention needs also to consider that other factors just can reach required film uniformity.For example, obtained to prevent that solid (as drug particles) from sedimentary stable suspension taking place in non-colloid is used.A kind of method provided by the invention is to make grain density (ρ _p) and density of liquid phase (ρ ₁) reach balance and increase the viscosity (μ) of liquid phase.With regard to isolating granule, as follows about the Stokes' law (Stokes law) of the final settling velocity (Vo) of rigid spheres in viscous fluid of certain radius (r):

V _o＝(2gr ^r)(ρ _p-ρ ₁)/9μ。

Yet when granule density is high, local granule concentration will influence local viscosity and density.The viscosity of suspension is the majorant (strong function) of fractional solid volume, and granule-granule and granule-liquid phase mutual effect will further hinder settling velocity.

The Stokes analysis shows the adding third phase, as dispersive air or nitrogen, can promote the stability of suspension.In addition, the increase amounts of particles can produce the precipitation of being obstructed based on fractional solid volume.In the particle suspension liquid of dilution, settling rate, v can be expressed as:

Wherein κ is a constant,

It is the volume fraction of dispersive thing phase.The granule increase that is suspended in the liquid phase can cause speed to reduce.Because particle size can influence granule-particulate mobile mutual effect, so the particle geometric shape also is a key factor.

Similarly, the viscosity of suspension depends on the volume fraction of dispersing solid.With regard to the diluted suspension of the spheroidal particle of no mutual effect, the viscosity of suspension can be expressed as:

μ/μ _o＝1+2.5φ

μ wherein _oBe the viscosity of continuous phase, φ is a fractional solid volume.When volume fraction was higher, the viscosity of dispersion can be expressed as:

Wherein C is a constant.

The viscosity of liquid phase is very crucial, and hope can be the viscoelasticity non-Newtonian fluid with low yield value of stress with the liquid improvement by the customization fluid composition.This and the static continuous phase equivalence of generation high viscosity.The fluid that forms viscoelasticity or highly structural is on good terms provides additional friction for solids precipitation.In addition, granule-granule is interacted drop to mental retardation control flocculation or assemble.Net effect is kept equally distributed thing phase exactly.

Aqueous phase toward suspension adds glue physical ability increase viscosity, can produce viscoelasticity and can give stability based on different hydrocolloid types, its concentration and particulate composition, geometry, size and volume fraction.Need by select in the high viscosity medium minimum actual grain size promptly＜500mm, control the particle size distribution of dispersive thing in mutually.Do not consider apparent viscosity, exist the elastomer of slight yield stress or low shear rate can reduce lasting stability yet.Can calculate the critical particle diameter by yield value of stress.Under the situation of isolating spheroidal particle, the maximum shear stress that precipitation produces in the medium of given viscosity is as follows:

τ _Maximum=3V μ/2r.

With regard to pseudoplastic fluid, the zero shear viscosity characterization the when viscosity in this shear stress scheme just in time is newton's platform (Newtonian plateau).

To inject the premix compositions of thin film casting machine for preparation, thereby and the stability of keeping the wet film stage form abundant solid form up to intensive drying with locking granule and substrate and keep homogeneity, steady suspension is an important feature.With regard to viscoelastic fluid system, the rheology that can obtain long-time as 24 hours stable suspension must balance each other with the demand to the high-speed film pouring operation.Ideal film should have shear thinning or pseudoplastic characteristics, and thus, viscosity can reduce with the increase of shear rate.Time dependence shear effect for example thixotropy also is favourable.Structural recovery and shear thinning behavior are key properties, make film have the ability that the oneself evens up when forming.

The rheology condition of the present composition and film is very strict.This is because of the stable particle suspension liquid of generation, for example 30-60 weight % in the viscoelastic fluid substrate that need all have the acceptable viscosity value in big range of shear rate.May experience 10-10 between mixing, suction and thin film casting cycle ⁵Second ^-1Shear rate, pseudoplastic behavior is a preferred implementation.

When thin film cast or coating,, also be a limiting factor therefore because rheological characteristic has the ability that forms required uniformity film.Shear viscosity, tensile viscosity, viscoelasticity, structural recovery can influence the quality of film.The illustrative example of pseudoplastic fluid of evening up shear thinning is as follows:

α ^(n-1/n)＝α _o ^(n-1/n)-((n-1)/(2n-1))(τ/K) ^1/n(2π/λ) ^(3+n)/nh ^(2n+1)nt

Wherein α is the surface wave amplitude, α _oBe initial amplitude, λ is the wavelength of surface roughness, and " n " and " K " all is viscosity power law index.In this example, the behavior of evening up is relevant with viscosity, with the reducing and increase of n, reduces with the increase of K.

Ideally, film of the present invention or film-forming composition can very fast recovery structures, that is, behind treated formation film, it can disintegrate or produces discontinuous aspect its structure and component uniformity.This structural very fast recovery can slow down solids precipitation and deposition.And ideal film of the present invention or film-forming composition are the pseudoplastic fluids of shear thinning.Consider the fluidic characteristic of this class, for example viscosity and elasticity can promote the formation and the uniformity of thin film.

Therefore, the uniformity of component mixture depends on many variablees.As described herein, the rheological behavior of the viscosity of described component, hybrid technology, the blend compositions that makes and wet casting film all is an importance of the present invention.In addition, also to further consider controlling particle size and grain shape.Ideal particle size is 150 microns or littler, for example 100 microns or littler.And this class granule can be spherical, and substantially spherical or non-sphere are as irregularly shaped particles or oval granule.It is desirable to oval granule or ellipsoid,, thereby can be maintained in the uniformity of membrane matrix because their sedimentary tendencies are lower than the precipitation tendency of spheroidal particle.

Can adopt many technology to prevent from telolemma, to carry bubble secretly at mix stages.In order to be provided at the composition mixture that does not have bubble formation in the final products basically, can adopt anti-foaming agent or surface tension reducer.In addition, preferably can also control mixing velocity, prevent from gas inspiration mixture is formed cavitation.At last, can also bubble be overflowed reduce bubble by before the film drying, mixture being left standstill sufficiently long a period of time.Ideal the inventive method is at first to form the film-forming components masterbatch that does not contain active component such as drug particles or volatile material such as flavored oils.Before being about to pour into a mould, described activating agent is added in the less masterbatch mixture.Therefore, described masterbatch premix can leave standstill the long period and need not to consider the unstability of medicine or other composition.

When formation contains film forming polymer and polar solvent, when also having the substrate of other additive and active component in addition, can finish through many steps.For example, whole compositions can be added together or can prepare premix.The advantage of premix is that all the components except activating agent can make up in advance, is being about to just to add activating agent before the film forming.This activating agent that can degrade to Long contact time water, air or another kind of polar solvent is even more important.

Fig. 6 shows a kind of be suitable for preparing premix, adding activating agent and film forming subsequently equipment 20.The described premix or the masterbatch 22 that will comprise film forming polymer, polar solvent and any other additive except that pharmaceutically active agents add masterbatch feed well 24.Should in the blender (not shown), form each component of premix or masterbatch 22, and then add in the masterbatch feed well 24.Then, with the masterbatch of scheduled volume through first dosing pump 26 and control valve 28 controlled give expect first and/or second blender 30,30 '.Yet, the present invention be not limited to adopt two blenders 30,30 ', can adopt any amount of blender suitably.And, the present invention be not limited to blender 30,30 ' any particular sorted, can adopt suitably as shown in Figure 6 parallel ordering and other ordering or the arrangement of blender, as parallel and successive series or combination.With the medicine of aequum or other composition such as flavoring agent by each blender 30,30 ' opening 32,32 ' addings expect in the blender.Hope can make premix or masterbatch 22 blender 30,30 ' in holdup time the shortest.Although medicine is disperseed in premix or masterbatch 22 fully, the long holdup time can make medicine leach or dissolving, and is especially true to soluble agents.Therefore, blender 30,30 ' littler than the elementary blender (not shown) that is used to form premix or masterbatch 22 usually can shorten the holdup time.Medicine mix with the masterbatch premix be enough to a period of time of even substrate is provided after, with a certain amount of even substrate through second dosing pump 34,34 ' be fed to dish 36.Described metering roll 38 has determined the thickness of film 42, and it is delivered to application roll.Final described film 42 is shaped on base material 44, transports through backing roll 46.

Though the appropriate viscosity uniformity of mixture and stable particle suspension and pouring procedure in the initial step that forms compositions and film to promoting that uniformity is very important, yet it is important too that wet film is carried out exsiccant method.Although these parameters and characteristic help initial uniformity,, when controlled quickly drying method can guarantee to make uniformity to remain to the film drying.

Then, ideal situation is not have outer gas stream on the end face (exposure) 48 at film as described herein or not under its condition that heats, adopt the dry wet film of the dry or controlled method for microwave drying in controlled bottom.Dry or the controlled microwave drying in controlled bottom can advantageously make the film released vapour and avoid the shortcoming of prior art.The conventional convection current air drying that begins from the top can make film begin drying from topmost, hinders fluid together as the steam of evaporation and the mobile barrier of hot-fluid such as dry heat energy thereby form, thereby can not adopt.The further release of steam when the exsiccant top section of this class hinders dry bottom portion as barrier, thus the heterogeneity film obtained.As mentioned above, some top stream can be with helping dry film of the present invention, but it can not cause can cause cause heteropical granule to move or film in the condition of chain reaction.If adopt the top air, it must balance each other with the bottom air drying and avoid heterogeneity and prevent that film from arching upward on transport tape.When the bottom air-flow plays main dry source, and top stream plays the time spent of doing of less important dry source, and top and bottom air-flow be balance suitably.The advantage of some top stream is to remove the steam of discharge from film, thereby helps whole dry run.Yet the exsiccant utilization in any top stream or top all needs the many factors of balance, includes but not limited to: the rheological characteristic of compositions and processed are in the factor of mechanical aspects.Also necessarily require flowing of any top fluid (as air) all can not suppress as described in the intrinsic viscosity of film-forming composition.In other words, described top stream can not be destroyed, be twisted or the surface of the described compositions of Physical Interference otherwise.And ideal air velocity will be lower than the yield value of film,, is lower than any level of force that can be moved into the liquid in the film composition that is.With regard to thin or low viscous compositions, must adopt low-flow speed.With regard to stiff or full-bodied compositions, can adopt higher air velocity.And, thereby lower can avoid the film made by compositions any of ideal air velocity arches upward or other moves.

And film of the present invention can contain the temperature sensitivity granule, as being volatile flavoring agent, maybe can have the medicine of low degraded temperature.At this moment, can reduce baking temperature and prolong suitable dry uniform films of the present invention drying time simultaneously.And, to compare with the top drying, the bottom drying also can cause lower temperature in the shed.Compare with the top drying, when the bottom is dry, evaporated vapor can be more easily with the heat band from film, thereby reduce temperature in the shed.The temperature in the shed that this class is lower can cause that usually drug degradation reduces and the loss of some volatilizer such as flavoring agent reduces.

And, can also after the cast of compositions or mixture is formed film, granule or microgranule be added in described film-forming composition or the substrate.For example, can be before desciccator diaphragm 42 granule be added film 42.Controllably granule is added on the film with measuring, makes it to be deposited on the film, granule is deposited on the film surface with controlling as the scraper (not shown) device of touching or touch the film surface by utilization gently at the edge by suitable technique.Other suitable but nonrestrictive technology comprises: utilizes and extends roller granule is placed on the film surface, and particle jetting is first-class to the film surface.Described granule can place on the one or both sides on film surface, that is, and and the end face on film surface and/or bottom surface.Ideal situation is that granule firmly is arranged on the film, as embedding in the film.And, fully embedding or embed in the film fully of this class granule in the ideal situation, but still be exposed to the film surface, as be partially submerged into or the situation of part embedded particles.

Described granule can be any useful organ sensation's agent, enamel, medicament or its combination.Ideal medicament is to hide medicament taste or controlled release.Useful organ sensation's agent comprises flavoring agent and sweeting agent.Useful enamel comprises breath freshener or Decongestant, as menthol, comprises the menthol crystal.

Although the inventive method is not limited to any exsiccant concrete instrument of above-mentioned ideal that can be used for, a kind of concrete useful drying instrument 50 as shown in Figure 7.Drying instrument 50 is the nozzle arrangement that hot fluid (such as but not limited to hot-air) guiding are positioned at film 42 bottoms on the base material 44.Hot-air enters the entrance point 52 of described drying instrument, moves toward air deflector 56 vertically upward as described in vector 54.The direction that described air deflector 56 change air move makes the upward force minimum to film 42.As described in Figure 7, when air flow through air deflector 56, enter and the chamber portion 58 and 58 ' time of the described drying instrument 50 of flowing through, air as vector 60 and 60 ' shown in be oriented in a tangential direction.Thermal current is tangent line with film 42 basically, thereby the probability that film arches upward when making drying reduces to minimum.Although illustrated air deflector 56 is rollers, also suitable other device and the geometry of adopting come local derviation air or hot fluid.And, the port of export 62 and 62 of described drying instrument 50 ' open downwards.This open downwards provide as vector 64 and 64 ' shown in downward power or downward velocity vector, thereby help to provide tractive or drag interaction to prevent that film 42 from arching upward to film 42.Arching upward of film 42 not only can cause non-homogeneous shape in film, can also cause that film 42 and/or base material 44 arch upward and make the processing of film 42 uncontrolled from process equipment.

Monitoring and controlling diaphragm thickness can provide the film of uniform thickness, thereby also help to produce uniform films.The thickness of film can be monitored with gauge such as beta thickness gauge (Beta Gauge).Gauge can be the terminal coupling of drying oven or drying tunnel at drying instrument with another gauge, is communicated with the opening of controlling and regulate applicator through feedback circuit, thus the uniformity of controlling diaphragm thickness.

Usually polymer and polar solvent by will suitably selecting, and required any active component or filler make up and prepare described film product.Solvent in the desirable combination accounts for total combination at least about 30 weight %.Should the substrate that this is combined to form be made film by roller coat, should carry out dry uniformity with the maintenance film by quick and controlled drying means then, more specifically say, be that non-self aggregation is evenly heterogeneous.The film that obtains should contain the following solvent of 10 weight % of having an appointment, the solvent that more desirably about 8 weight % are following, even following solvent and the following solvent of most desirably about 2 weight % of more desirably about 6 weight %.Described solvent can be water, polar organic solvent, includes but not limited to: ethanol, isopropyl alcohol, acetone, dichloromethane or its any combination.

Above-mentioned parameter also can influence the material selection of different component of the present invention such as but not limited to the consideration of rheological characteristic, viscosity, mixed method, pouring procedure and drying means.And the consideration that this class is selected suitable material makes the present composition, comprises medicine and/or beauty treatment dosage form or film product, and the medicine in the per unit area and/or the difference of cosmetic activity agent are no more than 10%.In other words, be no more than 10 weight % by the difference that makes the medicine that exists in the whole substrate and/or cosmetic activity agent and determine uniformity of the present invention.Ideally, described difference is below the 5 weight %, below the 2 weight %, below the 1 weight % or below the 0.5 weight %.

Film forming polymer

Described polymer can be water solublity, water-swellable, insoluble polymer, or the combination of one or more water solublity, water-swellable or insoluble polymer.Described polymer can comprise cellulose or cellulose derivative.The object lesson of useful water-soluble polymer includes but not limited to: poly(ethylene oxide) (PEO), amylopectin, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, Polyethylene Glycol, xanthan gum, Tragacanth, guar gum, acacin, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxy vinyl co-polymer, starch, gelatin and combination thereof.In some embodiments, adopt the combination of PEO and cellulosic polymer (as hydroxypropyl cellulose).The object lesson of useful insoluble polymer includes but not limited to: ethyl cellulose, Cellulose ethyl hydroxypropyl ether, cellulose acetate-phthalate, Hydroxypropyl Methylcellulose Phathalate and combination thereof.

Phrase used herein " water-soluble polymer " and variant thereof refer to be partially soluble at least water, preferably fully or most of water-soluble or absorb the polymer of moisture.The polymer that absorbs moisture is often referred to the water-swellable polymer.The used material of the present invention can have water solublity or water-swellable in room temperature and other temperature when being higher than room temperature.And described material can have water solublity or water-swellable under pressure below atmospheric pressure.Ideally, described water-soluble polymer is water solublity or the water-swellable polymer with at least 20 weight % water intakes.Also can adopt the water-swellable polymer of water intake with 25 weight % or higher percentage ratio.Film of the present invention or the dosage form made by this class water-soluble polymer should have enough water solublity, can dissolve when contacting with body fluid.

Other polymer that can be used for mixing film of the present invention comprises biodegradable polymer, copolymer, block polymer and combination thereof.The known useful polymer or the type of polymer that satisfy above-mentioned standard are: poly-(glycolic) (PGA), poly-(lactic acid) (PLA), poly-diox, poly-oxalate, poly-(α-ester), polyanhydride, poly-acetas, polycaprolactone, poly-(ortho esters), polyamino acid, poly-amino-carbon acid esters, polyurethane, Merlon, polyamide, poly-(alkyl cyanoacrylate) and composition thereof and copolymer.Other useful polymer comprises, the space polymers of L-and D-lactic acid, the copolymer of two (right-the carboxyl phenoxy group) propanoic acid and decanedioic acid, the decanedioic acid copolymer, caprolactone copolymer, poly-(lactic acid)/poly-(glycolic)/ethylene glycol copolymer, the copolymer of polyurethane and (poly-(lactic acid)), the copolymer of polyurethane and poly-(lactic acid), the copolymer of a-amino acid, the copolymer of a-amino acid and caproic acid, the copolymer of α-benzyl glutamic acid and Polyethylene Glycol, the copolymer of succinate and poly-(ethylene glycol), polyphosphazene, poly-hydroxyl-alkanoate and composition thereof.Binary and ternary system have also been considered.

Other concrete available polymer comprises with trade name Medisorb and those commercially available polymer of Biodel.Described Medisorb material can be designated as " poly (lactide-co-glycolide) " that contain " the 2-hydroxy polymer of propanoic acid, hydroxyl polymer-containing and hydroxyacetic acid " usually available from the E.I.Du Pont Company (Dupont Company) of Wilmington City, Delaware, USA State.4 kinds of these base polymers comprise lactide/glycolides 100L, think to have 338-347 100% lactide of fusing point of (170-175 ℃); Lactide/glycolides 100L, think to have 437-455 100% Acetic acid, hydroxy-, bimol. cyclic ester of fusing point of (225-235 ℃); Lactide/glycolides 85/15, think to have 338-347 85% lactide and 15% Acetic acid, hydroxy-, bimol. cyclic ester of fusing point of (170-175 ℃); And lactide/glycolides 50/50, think to have 338-347 50% lactide of fusing point of (170-175 ℃) and the copolymer of 50% Acetic acid, hydroxy-, bimol. cyclic ester.

Described Biodel material is represented the different polyanhydrides material of all kinds of chemical property.

Although can adopt various polymer, wish that selective polymer provided the viscosity of expection for mixture before drying.For example, if activating agent or other component are insoluble to selected solvent, then need to provide more full-bodied polymer to help keep uniformity.On the other hand, if described component dissolves in solvent, then preferably provide more low viscous polymer.

Described polymer has played important function aspect the film viscosity influencing.Viscosity is a kind of characteristics of liquids of the stability of control activating agent in Emulsion, colloid or suspension.Usually the viscosity of substrate changes in 000 centipoise at about 400-100, preferably is about 800-60,000 centipoise be most preferably 1,000-40,000 centipoise.Ideal one-tenth membrane matrix viscosity can increase after the beginning dry run fast.

Can regulate described viscosity according to the activating agent of selecting according to other component in the substrate.For example, if described component is insoluble to selected solvent, then can select suitable viscosity in case described component precipitation consequently influences the uniformity that makes film unfriendly.Can regulate described viscosity with different modes.In order to increase the viscosity of membrane matrix, can select to have more high molecular weight polymers or can add cross-linking agent, as calcium salt, sodium salt and potassium salt.Can regulate viscosity by attemperation or by adding viscosity increasing component.The component that can increase viscosity or stable emulsion/suspension comprises more high molecular weight polymers and polysaccharide and colloid, includes but not limited to: alginate, carageen polysaccharide, hydroxypropyl emthylcellulose, locust bean gum, guar gum, xanthan gum, dextran, arabic gum, gellan gum and combination thereof.

Also observe, some polymer that needs plasticizer could obtain the flexible film when using separately usually can combine, and also can obtain the flexible film when not needing plasticizer.For example, can obtain to have suitable plasticity and elasticity when coupling HPMC and HPC and be convenient to the flexible robust thin film making and preserve.Its flexible acquisition does not need other plasticizer or polyhydric alcohol.

Release-controlled film

Term " controlled release " refers to that activating agent discharges with the speed of chosen in advance or expection.This speed can change according to purposes.Ideal speed comprises fast or moderate release profiles and delay, continue or discharge in succession.Also considered the combination of release mode, strengthened release during as beginning, then reduced levels continues release bioactive agent.Also considered the pulsed drug release.

The polymer that is selected for film of the present invention can also make controllably disintegrate of activating agent.Can realize by the water-insoluble basically film that has mixed a period of time of after the activating agent that can discharge in the film is provided.Can realize by mixing various solubility or insoluble polymer, can also contain biodegradable polymer in the combination.Perhaps, the controlled release active particle through coating can be mixed in the easy molten membrane matrix, thereby after picked-up, realize the controlled release attribute of activating agent in digestive system.

Can provide the film of controlled release activating agent especially suitable in oral cavity, gingival sulcus, Sublingual and vaginal application.Because film of the present invention can be easily moistening on the ground that has mucosa or mucosa liquid and be adhered on it, thereby is particularly useful for these places.

Drug world recognizes for a long time, and giving can be more more convenient than giving repeatedly single dose with regular intervals with the single dose of drug of the long-time release of active ingredients of mode of control.Recognize that also it has the advantage of the blood Chinese medicine level that can keep lasting and stable for a long time to patient and clinician.The advantage of various sustained release formses is many known.Yet the manufacture method of the film of energy controlled release activating agent also has other advantage except the advantage of those known controlled-release pharmaceutical tablets.For example, owing to need not swallow thin film as tablet, so it is not easy to be sucked trachea absent-mindedly, thereby has increased patient's compliance.And some embodiment of film of the present invention is designed to adhere to oral cavity and tongue and control ground dissolving there.And thin film can not broken into pieces as controlled-release pharmaceutical tablet, thereby has avoided the abuse problem of medicine such as OxyContin.

The activating agent that the present invention adopts can mix in the film composition of the present invention of controlled release forms.For example, granule medicament can be used polymer (as respectively with trade name such as Aquacoat ECD and commercially available ethyl cellulose or the polymethacrylates of Eudragit E-100) coating.Drug solution also can be adsorbed onto on the polymeric material and mix in the film composition of the present invention.Other component such as fat and wax, and sweeting agent and/or flavoring agent also can be used in this class controlled release composition.

Described activating agent can hide through the sense of taste before mixing film composition, (be pursuant to the identical U.S. Provisional Application number express label of title that JIUYUE in 2003 was submitted on the 27th: EU552991605 US as the PCT application that is entitled as UniformFilms For Rapid Dissolve Dosage Form Incorporating Taste-Masking Compositions (mixing the uniform films that the sense of taste hides the rapid-dissolve dosage form of compositions) of awaiting the reply jointly, agent's docket number: 1199-15P) described, it is for referencial use to include this paper in full in it.

Activating agent

When activating agent is imported film,, therefore can determine the amount of activating agent described in the per unit area because film is equally distributed.For example, when film is cut into each dosage form, can very accurately know the amount of the activating agent in the described dosage form.This be because in the particular area amount of activating agent basically with another part film in the onesize area amount of activating agent identical.When described activating agent is a medicament when being medicine, the accuracy of dosage is especially favourable.

The active component that can mix film of the present invention includes but not limited to: medicinal and cosmetic activity agent, medicine, medicament, antigen or anaphylactogen such as ragweed pollen, brood cell, microorganism comprise that antibacterial, seed, oral cavity clean component such as chlorate or chlorite, flavoring agent, spice, enzyme, antiseptic, sweeting agent, coloring agent, spice, vitamin and combination thereof.

The active substance and the pharmaceutical composition that can contain various medicaments, biologically active in the dosage form of the present invention.The example of useful medicine comprises the ACE-inhibitor, anti-anginal drug, anti-arrhythmic, antasthmatic, anti-cholesterol medicine, analgesic, anesthetis, anticonvulsant, antidepressants, antidiabetic drug, anti-diarrhoeic prod, antidote, hydryllin, antihypertensive, the antibiotic medicine, the antilipoid medicine, anti-manic medicine, antinanseant, Aggrenox, the antithyroid goods, antineoplastic agent, antiviral agents, the acne medicine, alkaloid, products of amino acid, cough medicine, antigout drug (anti-uricemic drug), antiviral agents, short anabolism goods, whole body and non-general anti-infective, antineoplastic agent, antiparkinsonism drug, antirheumatic, appetite stimulator, biological response modifier, Hemoregulatory, the bone metabolism regulator, cardiovascular drug, central nervous system's stimulant, cholinesterase inhibitor, contraceptive, decongestant, food additive, dopamine-receptor stimulant, the endometriosis controlling agent, enzyme, remedial agent for erectile dysfunction, fertility factor, gastrointestinal drug, homeopathic therapeutic method's agent, hormone, hypercalcemia and hypocalcemia controlling agent, immunomodulator, immunosuppressant, migraine agent, the motion sickness therapeutic agent, muscle relaxant, obesity control agent, the osteoporosis agent, oxytocic, parasympatholytic, parasympathomimetic agent, prostaglandin, psychotherapy's agent, breathe agent, analgesic, smoking deterent such as bromocriptine and nicotine, sympatholytic, medicine trembles, the urinary tract medicine, vasodilator, laxative, antacid, ion exchange resin, antipyretic, appetite suppressant, expectorant, antianxiety drugs, antiulcerative, anti-inflammatory agent, coronary artery dilator, the brain expander, peripheral vasodilator, intend neurologic agent, analeptic, antihypertensive, vasoconstrictor, the migraine treatment agent, antibiotic, tranquilizer, psychosis, antineoplastic agent, anticoagulant, antithrombotic, sleeping pill, Bendectin, antinauseant, anticonvulsant, neuromuscular drug, blood glucose increasing and blood sugar lowering, thyroid and antithyroid drug, diuretic, spasmolytic, agent is speeded to delay in the uterus, antiadipositas drug, promoting erythrocyte generates medicine, antasthmatic, anti-tussive agents, mucolytic, DNA and genetic modification medicine and combination thereof.

Through considering that the example that can be used for active constituents of medicine of the present invention comprises antacid, H ₂-antagonist and analgesic.For example, can singly prepare and separate acid supplement with the calcium carbonate composition or with magnesium hydroxide and/or aluminium hydroxide coupling.And, antacid can with H ₂The coupling of-antagonist.

Analgesic comprises Opiate and opium derivant, as oxycodone (with

Commercially available), ibuprofen, aspirin, acetaminophen and or choosing contain the combination of caffeine.

Can be used for other preferred agents of the present invention as other preferred active component and comprise diarrhea medicine such as imodium AD, hydryllin, cough medicine, decongestant, vitamin and breath freshener.This paper considers that the suitable vitamin that uses comprises the known vitamin of any routine, such as but not limited to: vitamin A, B, C and E.Can contain Chang Danyong or coupling in the film composition of the present invention and treat flu, pain, fever, cough, hyperemia, runny nose and hypersensitive medicine, as acetaminophen, chlorphenamine maleate, dextromethorphan, pseudoephedrine HCl and diphenhydramine.

This paper also consider to use antianxiety drugs such as alprazolam (with

Commercially available); Psychosis such as Crow azoles flat (clozopin, with

Commercially available) and haloperidol (with Commercially available); Non-steroid antiinflammatory drug (NSAID) as the bicyclo-chlorfenac (with Commercially available) and etodolac (with

Commercially available), hydryllin such as loratadine (with

Commercially available), astemizole is (with Hismanal ^TMCommercially available), nabumetone (with

Commercially available) and clemastine (with

Commercially available); Bendectin example hydrochloric acid granisetron (with

Commercially available) and nabilone (with Cesamet ^TMCommercially available); Bronchodilator as

Salbutamol sulfate (with

Commercially available); Antidepressants example hydrochloric acid fluoxetine (with

Commercially available), sertraline hydrochloride (with

Commercially available) and paroxetine hydrochloride (with

Commercially available); Antimigraine as

ACE-inhibitor such as enalaprilat (with

Commercially available), captopril (with

Commercially available) and lisinopril (with

Commercially available); Sick medicine of Kang Aercihaimoshi such as nicergoline; And Ca ^H-antagonist such as nifedipine (with With Commercially available) and verapamil hydrochloride (with

Commercially available).

Remedial agent for erectile dysfunction includes but not limited to: can promote blood to flow to penis and influence the autonomic nerve activity, if can increase parasympathetic nervous (cholinergic) and the active medicine of minimizing sympathetic nerve (Adrenergic).Useful non-limiting medicine comprise 'Xiduofeng ' as

Non-in it reaches (tadalafils) as

Vardenafil, apomorphine as

Yohimbine Hcl as With Alprostadil as

Consider to be used for H commonly used of the present invention ₂-antagonist comprises that Cimetidine, ranitidine hydrochloride, famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, a sand are for fourth and roxatidine.

Active antacid composition includes but not limited to following: aluminium hydroxide, dihydroxyaluminum aminoacetate, glycine, aluminum phosphate, mincid, bicarbonate, bismuth aluminate, waltherite, bismuth subcarbonate, bismuth subgallate, basic bismuth nitrate, basic bismuth salicylate, calcium carbonate, calcium phosphate, citrate ion (acid or salt), glycine, Magnesium sulfate heptahydrate aluminum (hydrate magnesium aluminate sulfate), magaldrate (magaldrate), almasilate (magnesium aluminosilicate), magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids (milk solid), aluminum phosphate one calcium or aluminum phosphate dicalcium (aluminum mono-ordibasic calciumphosphate), tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, almasilate, tartaric acid and salt.

The pharmaceutically active agents that the present invention adopts can comprise anaphylactogen or antigen, such as but not limited to: the plant pollen of grass, tree or artemisiifolia; The animal scurf is promptly from the skin of cat and other fur-bearing animal and the little squama of alopecia; Insecticide is as dermatophagoides pteronyssinus, Apis and wasp; And medicine, as penicillin.

Can also add plant, medicinal herbs and mineral in the film.The example of plant includes but not limited to: root; Skin; Leaf; Stem; Flower; Fruit; Nicotiana tabacum L.; The Helianthi seed; Folium Nicotianae preparatum palm fibre (snuff) and combination thereof.

Antioxidant can also be added film to prevent especially heliosensitivity activating agent degraded of activating agent.

The described bioactive substance that the present invention adopts can comprise probiotics.Say that more specifically normal presence is in some antibacterial of tongue surface and throat back.This bacterioid is helped digest food by the protein that decomposes in the food.Therefore, ideal situation is that these antibacterials are mixed oral cavity of the present invention with in the film product.

Ideally also comprise the activating agent of treatment halitosis and relevant oral care disease, if can effectively suppress the activation of microorganism agent.Because halitosis may be owing to existing the anaerobe that can produce volatile sulfur compounds to cause in the oral cavity, therefore ideally can adopting the component that can suppress this quasi-microorganism.The example of this class component comprises antibacterial, as triclosan, chlorine dioxide, chlorate and chlorite etc.Using chlorite in oral care composition such as mouthwass and toothpaste specifically is that the method for sodium chlorite can be referring to United States Patent (USP) 6,251,372,6,132,702,6,077,502 and the U.S. disclose 2003/0129144, it is for referencial use all to include this paper in full in it.This class component is mixed with the effective dose of treatment halitosis and relevant oral disease.

The cosmetic activity agent can comprise breath freshening chemical compound such as menthol, and other flavoring agent or spice are in particular for those chemical compounds of oral hygiene, and the activating agent such as the quaternary ammonium base that are used for tooth and oral cavity cleaning.Can use seasoning reinforcing agent such as tartaric acid, citric acid, vanillin to wait the effect that strengthens flavoring agent.

Coloring agent also can be used to prepare film.This based colorant comprises food, medicine and cosmetics coloring agent (FD﹠amp; C), medicine and cosmetics coloring agent (D﹠amp; Or topical drug and cosmetics coloring agent (Ext.D﹠amp C); C).These coloring agent are dyestuffs, their corresponding color lakes, and some natural and deutero-coloring agent.The color lake is the dyestuff that is absorbed on the aluminium hydroxide.

Other example of coloring agent comprises known azo dye, organic or inorganic pigment, or the coloring agent of natural origin.Preferred inorganic pigments, as ferrum or titanyl compound, these oxides are with about 0.001-10% of all components weight, and preferably the concentration of about 0.5-3% adds.

Can select natural or synthetic baste to serve as flavoring agent.The extract that comprises volatile oil, synthetic flavored oils, seasoning aromatic, oil, liquid, oleoresin or plant, leaf, flower, fruit, stem and combination thereof in the illustrative list of this class material.Comprise Oleum menthae, cocoa and citrus oils such as Fructus Citri Limoniae, orange, Fructus Vitis viniferae, Citrus aurantium Linn. and grapefruit in the non-limiting and representative example tabulation, and the fruit elite comprises Fructus Mali pumilae, pears, peach, Fructus Vitis viniferae, Fructus Fragariae Ananssae, Fructus Rubi, Fructus Pruni pseudocerasi, Lee, Fructus Ananadis comosi, Fructus Pruni or other fruity flavoring agent.

Can add the film that contains flavoring agent thereby heat or cold beverage or soup through seasoning is provided.These flavoring agents include but not limited to: tea and soup flavoring agent be beef and Carnis Gallus domesticus taste for example.

Other useful flavoring agent comprises aldehyde and ester, as benzaldehyde (Fructus Pruni pseudocerasi, Semen Armeniacae Amarum), citral is α citral (Fructus Citri Limoniae, a Citrus aurantium Linn.), neral, that is, β citral (Fructus Citri Limoniae, Citrus aurantium Linn.), n-capric aldehyde (orange, Fructus Citri Limoniae), aldehyde C-8 (citrus fruit), aldehyde C-9 (citrus fruit), aldehyde C-12 (citrus fruit), tolyl aldehyde (Fructus Pruni pseudocerasi, Semen Armeniacae Amarum), 2,6-dimethyl octanol (green fruit) and 2-laurylene aldehyde (Citrus, Fructus Citri tangerinae) and combination thereof etc.

Described sweeting agent can be selected from following non-limiting tabulation: glucose (corn syrup), dextrose, Nulomoline, fructose and combination thereof; Glucide and its various salt are as sodium salt; Dipeptide sweetener is as the aspartame; Dihydrochalcone chemical compound, glycyrrhizin; Stevia Rebaudiana(Stevioside); The chlorinated derivative of sucrose is as sucralose; Sugar alcohol is as Sorbitol, mannitol, xylitol etc.It is also conceivable that hydrogenated starch hydrolysates and synthetic sweetener 3,6-dihydro-6-methyl isophthalic acid-1-1,2,3-Evil thiazine-4-ketone-2, the 2-dioxide specifically is the sweeting agent of its potassium salt (acesulfame potassium) and sodium thereof and calcium salt and natural reinforcement, as Lo Han Kuo.Also can use other sweeting agent.

When activating agent mixed in solvent with polymer, formed matrix type depended on the dissolubility of described activating agent and polymer.If described activating agent and/or polymer dissolve in selected solvent, can form solution so.Yet if described component is soluble, substrate can be divided into Emulsion, colloid or suspension so.

Dosage

It is very wide that film product of the present invention can hold the quantitative range of active component.No matter required dosage is high or extremely low, and film can both provide exact dose (size and the initial concentration of activating agent in polymer/water combination by film are determined).Therefore, according to the type of activating agent that mixes film or pharmaceutical composition, described active dose can should or be low to moderate the microgram scope up to about 150mg up to about 300mg, or any amount between them.

The high homogeneity of film has determined film product of the present invention and method to be very suitable for dynamical low-dose drugs.Therefore, should adopt low-dose drugs, especially have more the racemic mixture of the activating agent of usefulness.

Anti-tacking compositions

Can add antiplastering aid in the film composition of the present invention in the past, as lubricant, antitack agent and fluidizer.Antiplastering aid can be for example by reducing in the extrusion process with the adhesion of mould and reducing when giving described dosage form and the adhesion of oral cavity maxillary helps improve the fluid properties of material.

When using film, granule adheres on the maxillary of oral cavity easily.This is unfavorable for the film that contains bitterness medicine such as dextromethorphan, and this is because adhered particles is left medicine and can be made user feel more bitter.Add that antiplastering aid can reduce and the adhesion of oral cavity maxillary in the film, thus the bitterness of feeling when effectively alleviating the user use.

Antiplastering aid can also reduce film and intermembranous coefficient of friction, is the problem that the film bar sticks to each other thereby alleviate membrane amount unit.Say that more specifically in multiple film packing, the film bar piles up each other.Mix antiplastering aid and can make when in packing, taking out each unit, can slide glibly each other between each film bar.

The example that can be used as the proper lubrication agent of antiplastering aid includes but not limited to: stearate, as magnesium stearate, calcium stearate and sodium stearate; Stearic acid; Hydrogenated vegetable oil; Talcum; Wax; Stearoyl stearowet; Boric acid; Sodium benzoate; Sodium acetate; Sodium chloride; The DL-leucine; Macrogol 4000; Polyethylene glycol 6000; Enuatrol; Sodium lauryl sulfate; Lauryl sulfate magnesium and combination thereof.

The example of suitable antitack agent includes but not limited to: Talcum; Corn starch; Cab-O-Sil; Gas phase micropowder silica gel (syloid); The DL-leucine; Sodium lauryl sulfate; Metallic stearate and combination thereof.The example of suitable glidant includes but not limited to: Talcum; Corn starch; Cab-O-Sil; The gas phase micropowder silica gel; Aerosol and combination thereof.

Some embodiments of the present invention comprise uses fat and/or wax as antiplastering aid.

Use vitamin E as the suitable antiplastering aid of another kind in some embodiments of the present invention.Vitamin E can be simultaneously as active component in antiplastering aid and the film.Should adopt vitamin E TPGS (dextrorotation alpha tocopherol cetomacrogol 1000 succinate).Vitamin E TPGS is a kind of watermiscible vitamin E derived from natural origin.Compare with its other form, vitamin E TPGS is easier to absorb.In addition, vitamin E TPGS can bring taste to film hardly.Vitamin E TPGS can be used for solution, for example 10% or 20% aqueous solution.Vitamin E TPGS is particularly useful for reducing film viscosity, makes it to be not easy to adhere on the oral cavity maxillary of user.The content of vitamin E can account for the 0.01-20% of composition weight.

The content of antiplastering aid accounts for the 0.01-20% of film composition weight usually.Say that more specifically the content of antiplastering aid can account for the 0.01-10% of film composition weight, even more specifically say, account for the 0.25-5% of film composition weight.

Can also adopt the antiplastering aid combination.For example, in some embodiments of the present invention, can adopt the combination of stearate such as magnesium stearate and silicon dioxide.Particle mean size is the silica product of 4.5 μ m, and SIPERNAT500LS is applicable to herein (commercially available by Degussa).The combination of magnesium stearate and silicon dioxide can provide the fluidizer of improvement, that is, help the film bar in the packing to slide glibly each other.Therefore, in some embodiments, the content of magnesium stearate accounts for the 0.1-2.5% of film composition weight, and the content of silicon dioxide accounts for the 0.1-1.5% of film composition weight.This class combination of antiplastering aid can be used for containing in the various types of films of various flavoring agents and/or activating agent.

In some embodiments, described film composition itself just contains antiplastering aid.For example, can form the single or multiple lift film that contains antiplastering aid.Multilayer film for example, can comprise two-layer, three layers or the more multi-layered film that contact with each other basically.In some embodiments, described rete can be laminated to each other.Antiplastering aid may reside in one or more layers of multilayer film.For example, some embodiments can comprise duplicature, and wherein one deck contains antiplastering aid.Some embodiments can comprise trilamellar membrane, and wherein except that the internal layer or intermediate layer of described trilamellar membrane, each skin all contains antiplastering aid.With this, can form various dissimilar combination layers.

Perhaps, in some embodiments, the compositions that is used for the coated film outer surface can contain antiplastering aid.For example, can will wet or the antiplastering aid of dry coating (as containing sugar or sugar-free coating) form is used for film.Can adopt any conventional method (such as but not limited to: dip coated, spraying coating, dust or fluid bed) antiplastering aid coated film.Can be coated with one or more films surface.In some embodiments, described anti-stick coating can be used for base material,, but not be directly used in film itself as the film backing.When backing removes film, described anti-stick coating can adhere on the film.

Anti-foam and skimming compositions

Can also use anti-foam and/or skimming component in the film of the present invention.These components help air, as air pocket, discharge described film-forming composition.As mentioned above, this air pocket may cause forming non-homogeneous film.A kind of anti-foam that is particularly useful and/or defoaming agent are simethicone.Yet the present invention is not limited to this, can also use other anti-foam and/or defoaming agent.

Simethicone is generally used for medical field treatment baby's flatulence or stomachache.Simethicone is a kind of mixture of linear siloxane polymers of the exhaustive methylation that contains polydimethylsiloxane repetitive stable through trimethicone endcapped unit and silicon dioxide.It contains the polymethyl siloxane of 90.5-99% and the silicon dioxide of 4-7% usually.Described mixture is water-fast Lycoperdon polymorphum Vitt, translucent thick liquid.

When disperseing in water, simethicone can scatter at the water surface, forms the low surface tension thin film.Like this, simethicone can reduce the surface tension of foam gas (as foam bubble) in the solution, and they are broken.The dual function of water medium oil and alcohol has been imitated in the effect of simethicone.For example, because the density of oil-based liquid is littler than the density of aqueous solution, therefore any residual bubble all can rise to the surface and faster and more easily dissipation in oily solution.On the other hand, known alcohol/aqueous mixtures can reduce the surface tension that water density can reduce water again.Therefore, any bubble that remains in the mixed solution also can dissipate at an easy rate.Simethicone solution has the advantage of above-mentioned two aspects concurrently.It can reduce the surface energy that remains in any bubble in the aqueous solution, also can reduce the surface tension of aqueous solution.Owing to have the function of this uniqueness, make simethicone have fabulous anti-foam, can be used for physiology method (anti-flatulence) and need remove in any externalist methodology of bubble in the product.

In order to prevent to form bubble in the film of the present invention, can under vacuum condition, mix.Yet, in case described blend step is finished, film is got back under the normal atmosphere (An) condition, import gas again or make it and contact with mixture.Under many situations, minute bubbles can be residued in this polymeric adhesive solution once more.Simethicone is mixed the formation that bubble can be alleviated or eliminate to film-forming components basically.

Simethicone can about 0.01-5.0 weight %, and the better 0.05-2.5 of being about weight % and the most desirable content that is about 0.1-1.0 weight % add in the film forming mixture as antifoaming agent.

Or select component

Various other components and implant can also be added film of the present invention.These can include but not limited to: surfactant; Help to make the plasticizer of each component compatibility in the mixture; Polyhydric alcohol; Antifoaming agent, as contain the chemical compound of silicone, it creates more level and smooth film surface by making film discharge oxygen; And thermosetting cement, as pectic substance, antler glue and gelatin, help to keep each component dispersibility.

The various additives that can mix the present composition can provide various function.The example of various additives comprises excipient, lubricant, buffer agent, stabilizing agent, foaming agent, pigment, coloring agent, filler, extender, sweeting agent, flavoring agent, spice, release regulator, adjuvant, plasticizer, incremental dose, releasing agent, polyhydric alcohol, granulating agent, diluent, binding agent, buffer, absorbent, fluidizer, binding agent, antitack agent, acidulant, softening agent, resin, demulcent, solvent, surfactant, emulsifying agent, elastomer and composition thereof.These additives can add with active component.

Useful additive comprises, gelatin for example, vegetable protein such as Helianthi albumen, soybean protein, cottonseed protein, Semen arachidis hypogaeae protein, Semen Vitis viniferae albumen, lactalbumin, lactalbumin isolate, haemproteins, egg protein, the protein of acroleic acid esterification, water soluble polysaccharide such as alginate, carageen polysaccharide, guar gum, agar-agar, xanthan gum, gellan gum (gellan gum), arabic gum and relevant glue (Ficus elastica, karaya, tragacanth), pectin, water solublity derivative fibre element: alkylcellulose, hydroxy alkyl cellulose and hydroxyalkyl alkylcelluloses are as methylcellulose, hydroxy methocel, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose, HBMC, cellulose esters and hydroxy alkyl cellulose ester such as cellulose acetate-phthalate (CAP), hydroxypropyl emthylcellulose (HPMC); Carboxyalkyl cellulose, carboxyalkyl alkylcellulose, carboxyalkyl cellulose ester such as carboxymethyl cellulose and their alkali metal salt; Water-soluble synthetic polymer such as polyacrylic acid and polyacrylate, polymethylacrylic acid and polymethacrylates, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), PVY/ vinyl acetate copolymer and poly-.beta.-methylacrylic acid; The same gelatin that also has phthalate that is fit to, gelatin succinate, cross-linked gelatin, lac, water-soluble chemical derivatized starch, cation modified acrylate and for example have uncle's amino or can be the methacrylate of tetrad when season amino (as diethyllaminoethyl), needs; With other similar polymer.

This class extender or to select addition can be any amount, ideal range is up to about 80%, ideally is about 3-50% and better scope is the 3-20% of all components weight.

Other additive can be an inorganic filler, as the oxide of magnesium, aluminum, silicon, titanium etc.Its ideal concentration is about the 0.02-3 weight % of all components weight, ideally is about 0.02-1%.

The example of other additive is a plasticizer, comprise that the concentration range to account for polymer weight 0.5-30% and ideally to be about 0.5-20% adds polyalkylene oxides, as Polyethylene Glycol, polypropylene glycol, polyethylene propylene glycol, the organic plasticizer of low-molecular-weight, as glycerol, glycerol Monoacetate, diacetin or triacetate, vinegar essence, Polysorbate, spermol, propylene glycol, Sorbitol, diethyl sulfosuccinate sodium, triethyl citrate, tributyl citrate etc.

Can also add other chemical compound and improve the flowability of starch material, as ideal situation be hydrogenated form especially at room temperature be solid animal or plant fat.The desirable fusing point of these fat is 50 ℃ or higher.Preferred C ₁₂-, C ₁₄-, C ₁₆-, C ₁₈-, C ₂₀-and C ₂₂The triglyceride of-fatty acid.Can not add extender or plasticizer and add separately fat, and can be advantageously add separately or with glycerol list and/or dibasic acid esters or phospholipid especially lecithin.Ideal glycerol list and dibasic acid esters are derived from above-mentioned C ₁₂-, C ₁₄-, C ₁₆-, C ₁₈-, C ₂₀-and C ₂₂All kinds of fat of-fatty acid.

Total consumption of fat, monoglyceride, glycerol dibasic acid esters and/or lecithin accounts for the about 5% of total composition weight at most, preferably is about 0.5-2%.

Also be suitable for adding silicon dioxide, calcium silicates or the titanium dioxide that concentration accounts for the 0.02-1% of total composition weight.These chemical compounds play the effect of thickening agent.

The consumption of these additives is enough to realize intended purposes separately.Usually, the combination of some can change the whole release profiles of active component in these additives, can be used to regulate promptly hinder or quicken discharge.

Lecithin is a kind of surfactant of the present invention that can be used for.The feeding coal of lecithin can be about 0.25-2.00 weight %.Other surfactant, i.e. surfactant includes but not limited to: spermol, sodium lauryl sulfate, ICI Americas Inc (ICI Americas, Inc) commercially available Spans ^TMAnd tween ^TMCan also adopt the oil of ethoxylation, comprise the Oleum Ricini of ethoxylation, commercially available as BASF AG

EL.Carbowax ^TMStill the another kind of regulator very useful to the present invention.Can adopt tween ^TMOr the combination of surfactant realizes required hydrophilic-lipophilic balance (" HLB ").Yet the present invention can not need to adopt surfactant, and film of the present invention or film-forming composition can be substantially free of surfactant but still can provide uniform properties required for the present invention.

Adding dextrosan in the film of the present invention can be more favourable.Dextrosan is a kind of filler and solubilizing agent, that is, its energy reinforcing membrane is at intraoral dissolution time.

The definite purpose that can improve other regulator of operation of the present invention and product of applicant is that all other regulators of this class are included in the scope of the present invention of this paper prescription.

Other composition comprises makes film be easy to be shaped and the common binding agent useful to the quality of film.The non-limitative example of binding agent comprises starch, pre-gelatinized starch, gelatin, polyvinyl pyrrolidone, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyacrylamide, Ju Yi Xi oxazolidinone and polyvinyl alcohol.

Film forming

Film of the present invention must be in flakes before dry.When mix required component form comprise the multicomponent substrate of polymer, water and activating agent or other required component after, as multicomponent substrate as described in pushing, be coated with, sprawl, pour into a mould or drawing, sheet or film are made in described combination by any known method in this area.Multilayer film if desired can make up by more than one of coextrusion each component that contains identical or different compositions and realize.Can also make multilayer film by certain combination being coated with, sprawling or be poured on the rete that has been shaped.

Although can adopt various film technique, ideal situation is to select a kind of method that can prepare flexible film, as the reverse roll coating process.The pliability of film make diaphragm can preserve or cut into each dosage form before wind up and transport.In other words all right self-supporting of ideal film perhaps can not keep its integrity and structure when having independent holder.And, but film of the present invention can be selected from edible or digesting material.

In order to form film of the present invention, coating or pouring procedure are particularly useful.Especially when the needs multilayer film, concrete example comprises reverse roll coating, intaglio plate coating, immerse or dip coated, measuring stick or Meyer (Meyer) rod is coated with, slit mould or extrusion coated, crack or knife-over-roll coating (gap or knife over roll coating), airblade coating, curtain coating or its combination.

When according to the present invention during film forming, adopt print roll coating or be ideal especially more specifically for reverse roll is coated with.This method can control and make the film that obtains to have the desirable uniformity of the present invention admirably.In this method, described coating material is put on the application roll quantitatively by the slit that accurately is arranged between metering roll and its following application roll.During near described coating material is sent to application roll support roller, its can transfer to base material from application roll.3 rollers and 4 roller methods all are in daily use.

The intaglio plate coating process relies on the dandy roll that moves in the coating fluid to carry out, and rag point on the roller or the applied material of line are filled.Excessive coating material on the roller is wiped off with doctor blade, can be deposited on the base material in the time of then between coating material is by dandy roll and compression roll.

Photogravure is very common, and wherein coating material was deposited on the intermediate calender rolls earlier before transferring to base material.

Immerse or the simple procedure of dip coated in, base material is impregnated under the normal condition in the low viscous coating fluid, so as described base material when exposing liquid level coating material can flow back in the pond.

In the metering roll coating process,, base material is deposited on the base material when having excessive coating material during by the pond roller.Described wire-wound metering roll is sometimes referred to as Meyer rod (Meyer Bar), can stay the coating material of aequum on base material.Described amount is determined by the diameter of rod with line.

In the slit modeling method, arrive on the base material by gravity or under the pressure coating material being extruded slit.If coating material is 100% solid, this method just is called " squeezing and pressing method ", and in this case, linear velocity can be more much higher than extrusion speed usually.Can guarantee that like this coating layer is thin more a lot of than slot width.

In crack or the knife-over-roll method, coating material is applied on the base material, passes through " crack " between " scraper " and the support roller then.Along with passing through of coating material and base material, excess stock is scraped.

Airblade coating is that coating material is applied to base material, through the strong injection of air knife excess stock " is blown off ".This method can be used for the aqueous coating material.

In curtain formula coating process, the continuous coating material curtain that the bottom has the liquid pool generation of slit falls within two slits between conveyer belt.Object to be coated along conveyer belt with the controlled velocity process, thereby its upper surface can be received coating material.

The drying of film

Described drying steps also is to keep the inhomogeneity key factor of described film composition.When the viscosity that does not have thickening composition or compositions for example was controlled by selective polymer, component was easier to gathering or coalescent in the film, and select for use controlled drying means to be even more important this moment.Film forming or the choosing method with exact dose that need not controlled drying steps is a casting film on predetermined groove.Adopt this mode,,, can not make activating agent move to contiguous dosage form although therefore component can be assembled because each groove itself all defines dosage device.

, can realize during controlled or quickly drying method when needs by the whole bag of tricks.The whole bag of tricks that can adopt comprises those methods of needs utilization heating.Remove the liquid carrier in the striping in a certain way, to keep the uniformity that wet film has, the non-self aggregation of perhaps more specifically saying so is evenly heterogeneous.

Ideal situation is to carry out drying from the film bottom to the film top.During the primary solidification that forms the solid viscoelastic structure, ideally the film top does not have the air communication mistake basically.This can occur in several leading second in, as about 0.5-4.0 minute of drying process.The dry film end face that can prevent that the conventional drying method from often causing of control destroys and the phenomenon that forms again in this way.Can realize by forming film and it being placed on the end face on the surface with end face and bottom surface.Then, earlier the film bottom surface is heated evaporation to be provided or to remove the necessary energy of liquid carrier.Carrying out exsiccant film in this way can faster drying, even with the air drying film or compare also like this with the drying that the conventional drying means are carried out.Different with the edge with the at first dry end face of air drying film, the central authorities and the edge that carry out exsiccant film by heated base obtain drying simultaneously.Do like this and can also prevent with the normal composition deposited phenomenon that takes place of the exsiccant film of conventional means.

The film baking temperature is about 100 ℃ or lower, and ideal is about 90 ℃ or lower, the most desirablely is about 80 ℃ or lower.

Can use separately or comprise control with the method for the another kind of above-mentioned other control method coupling control drying process and regulate the interior humidity of the drying equipment of desciccator diaphragm.In this way, can avoid the too early drying of film end face.

In addition, also find suitably to control the length of drying time, promptly thermal sensitivity and the volatility with some component especially flavored oils and medicine balances each other.Can make the length and the speed of energy, temperature and conveyer belt coordinate to adapt to this activating agent mutually, and loss, degraded or ineffectivity that will telolemma drop to minimum.

The object lesson of suitable drying means is disclosed by Magoon.The method of a kind of dry pulp of Magoon specific design.Yet the inventor is used to prepare thin film with this technology.

The method and apparatus of Magoon all is based on the interesting characteristic of water.Although water can by portion within it and and the external world between conduction and convection current carry out energy delivery, water can only be in water and to the water Propagation of Energy.Therefore, the equipment of Magoon comprises that the infrared radiation of placing pulp can see through the surface.Following and the temperature control pond on described surface contacts.Described pond temperature should be controlled at the temperature a little less than the water boiling temperature.When wet pulp places on this equipment surface, produce " refractance window ".This means that infrared energy sees through the surface and can only pass to by the occupied surf zone of pulp, and can only provide energy herein up to the pulp drying.The equipment of Magoon can the accumulative efficient drying of membrane component take place in minimizing provides film of the present invention in the time.

The original depth of film is about 500-1,500 μ m, or about 20-60 mil, and dried thickness is about 3-250 μ m, perhaps is about the 0.1-10 mil.The thickness of ideal desciccator diaphragm is about the 2-8 mil, the better 3-6 mil that is about.

The utilization of thin film

Thin film of the present invention all is well suited for many application.The high homogeneity of membrane component especially is fit in conjunction with medicament them.And, can select to make film can have one period resolving time to the polymer that is used to make up film.The variation of film resolving time or prolongation can realize the control to the activating agent rate of release, thereby obtain to continue the delivery system of release.In addition, can activating agent be administered to any of multiple body surface, especially comprise the surface of mucosa with film, as in oral cavity, anus, vagina, eye, skin surface or the body as wound surface during the surgical operation and similar surfaces.

Film can be used for the orally give activating agent.Can pass through the above-mentioned film of preparation, and they be put into the mammal oral cavity finish.Can prepare film, and with its adhere to second or supporting layer on, use (promptly putting into the oral cavity) before with described film from second or supporting layer peel off.Can film be adhered on any in preferred water-fast those supports known in the art or the back lining materials with binding agent.If the use binding agent should can absorb and the food-grade adhesive that can not change activating agent character in use.The mucoadhesive compositions is particularly useful.Described film composition itself is exactly mucoadhesive in many cases.

Described film can be used for mammal Sublingual or tongue.When needing, can be preferably corresponding to the concrete film shape of tongue shape.Thereby film can be cut into corresponding to the film limit at tongue rear portion than shape corresponding to the forward film length of side of tongue.Particularly, desirable shape can be a triangle or trapezoidal.Ideal film can adhere on the oral cavity preventing that film from running out of the oral cavity, and discharges more activating agents when film dissolves in the oral cavity.

Can rapidly-soluble nature during the another kind of applications exploiting film contact liq of film of the present invention.Can pass through film produced according to the present invention, it be put into liquid make its dissolving, and activating agent is introduced liquid.This can be used for preparing the liquid dosage form of activating agent, or beverage is carried out seasoning.

Ideal situation be with film of the present invention be packaged in the packing of the secluding air of sealing and moisture with the protection activating agent can oxidation, hydrolysis, volatilization and interact with environment.As shown in Figure 1, packaged dosage units 10 comprises being packaged in the bag separately or between paper tinsel and/or the film 12 of 14 of plastics lamination sheets.As shown in Figure 2, the bag 10,10 ' can interconnect through peelable or porous seam 16.Bag 10,10 ' can be packaged into volume as shown in Figure 5 or pile up as shown in Figure 3, and sell with medicine box as shown in Figure 4.Described medicine box can contain a whole set of medicine of usually leaving at planned treatment, but thin film and packing make this medicine box littler and more convenient than the conventional bottle that is used to place tablet, capsule and medicinal liquid.And in a single day film of the present invention contacts and can dissolve immediately with saliva or mucosa district, need not water medicament is swept away.

This class dosage unit group should be packaged into together according to scheme or the treatment (as supply 10-90 days) that concrete therapy is advised.Each film can be packaged on the backing, tears off during use.

More fully embody feature and advantage of the present invention by following illustrative embodiment, and can not think restriction any way of the present invention.

Embodiment

Embodiment 1-2:

Prepare the thin, water soluble film composition with the described amount of table 1.Specifically, add vitamin E in the compositions 1 as antiplastering aid and various other component.Compositions 2 contains and compositions 1 similar component, but does not contain vitamin E.

Table 1

¹Germania sweeting agent (Magna Sweet) available from Ma Fu international corporation (Mafco Worldwide Corp).

²10% solution that contains 0.39g vitamin E and 3.51g water

³Available from thousand chemical company (Millennium Chemicals) N-ethyl-right-terpane-3-carboxylic acid amides coolant

⁴Available from three pure companies (Sentry)

Make it combination up to the thing that is uniformly mixed by mixing the above-mentioned component that is used for each compositions, pour into a mould film forming then.Specifically, with the K Control Coater that have 350 microns level and smooth rods with described solution casting to release paper (available from gray(Gy) husband paper and the (GriffPaper﹠amp of film company; Film)).Then about 80 ℃ with dry about 10 minutes of film.Compositions 1 is dried to water content is about 2.68%, compositions 2 is dried to water content is about 3.35%.

Detect the various character of described desciccator diaphragm, comprise how long and measure the pliability of film by bend test measure film by solubility test is dissolved in the oral cavity needs.In addition, observing film will present the trend of viscosity and stick at user oral cavity maxillary in the oral cavity trend on the flat board.

In order to detect rate of dissolution, the diaphragm of about 20 * 100mm of heavy 2.85g is dipped in the about 50mm depths in 32.5 ℃ the pond.Measure the film dissolving and be divided into two needed times (in second).

Also film has been carried out bend test, i.e. 180 ° of bend tests.Place moisture analyzer (available from the HR73 moisture analyzer of Ma Te Toledo (Mettler Toledo)) to obtain its moisture percentage ratio desciccator diaphragm, after 80 ℃ of dryings, remove any solvent (as water) that remains in the film according to the present invention.Then film is folded into about 180 °, observes the situation of breaking.When bending, can be defined as failure by disruptive film.If film does not break during bending, the weight of the film landing 200g from about 8.5mm eminence toward described bending.Disruptive film is confirmed as failure, and it is qualified that those do not have disruptive film to confirm as.Yet, should be noted that this flexibility test is a kind of extreme test.Still can think that the film of in test failure belongs to the interior feasible film of the scope of the invention.More specifically say, may not need the extreme pliability of this class in some applications.

Place before the moisture analyzer and afterwards compositions 1 and 2 films all show enough intensity, good resistance to rupture, and passed through 180 ° of bend tests, can with in dissolve on tongue to fast speed.The compositions 1 that contains vitamin E does not have viscosity in the oral cavity, can not adhere to user oral cavity maxillary.2 of compositionss that do not contain vitamin E are opposite.Compositions 2 shows viscosity, can adhere to the oral cavity maxillary.

Embodiment 3-243:

Be combined with as the silicon dioxide of antiplastering aid and the water-soluble film of magnesium stearate with the described content preparation of table 2.More specifically say, as shown in the table, various silicon dioxide and magnesium stearate combination are mixed in the various film composition.

Table 2

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				3	Acid agent (SOURS)	1.5	2.0
4	Acid agent (SOURS)	1.5	2.0
				5	Acid agent (SOURS)	1.5	2.0
6	Acid agent (SOURS)	1.5	2.0
				7	Acid agent (SOURS)	1.5	2.0
8	Acid agent (SOURS)	1.5	2.0
				9	Acid agent (SOURS)	1.5	2.0
10	Acid agent (SOURS)	1.5	2.0
				11	Acid agent (SOURS)	1.5	2.0
12	Acid agent (SOURS)	1.5	2.0
				13	Acid agent (SOURS)	1.5	2.0
14	Acid agent (SOURS)	1.5	2.0

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				15	Benzocaine/menthol	1.5	1.5
16	Benzocaine/menthol	1.5	1.5
				17	Benzocaine/menthol	1.5	1.5
18	Benzocaine/menthol	1.5	1.5
				19	Benzocaine/menthol	1.5	1.5
20	Acid agent (SOURS)	2	2.5
				21	Acid agent (SOURS)	1.5	2
22	Acid agent (SOURS)	1.5	2
				23	Acid agent (SOURS)	1.5	2
24	Acid agent (SOURS)	1.5	2
				25	Acid agent (SOURS)	1.5	2
26	Acid agent (SOURS)	1.5	2
				27	Acid agent (SOURS)	1.5	2.5
28	Acid agent (SOURS)	1.5	2.5
				29	Acid agent (SOURS)	1.5	2.5
30	Acid agent (SOURS)	1.5	2.5
				31	Acid agent (SOURS)	1.5	2
32	Acid agent (SOURS)	1.5	2
				33	Acid agent (SOURS)	1.5	2.5
34	Acid agent (SOURS)	1.5	2.5
				35	Acid agent (SOURS)	1.5	2.5
36	Acid agent (SOURS)	1.5	2.5
				37	Acid agent (SOURS)	1.5	2.5
38	Acid agent (SOURS)	1.5	2.5
				39	Acid agent (SOURS)	1.5	2.5
40	Acid agent (SOURS)	1.5	2.5
				41	Energy/healthy supplement 2	1	2
42	Energy/healthy supplement 2	1	2
				43	Energy/healthy supplement 2	0.9	1
44	Energy/healthy supplement 2	1.15	1
				45	Energy/healthy supplement 2	1	1
46	Energy/healthy supplement 2	0.75	1
				47	Energy/healthy supplement 2	1	1.5
48	Energy/healthy supplement 2	1	1
				49	Energy/healthy supplement 2	0.75	1
50	Energy/healthy supplement 2	1	1
				51	Energy/healthy supplement 2	1	1
52	Energy/healthy supplement 2	1	1
				53	Energy/healthy supplement 2	1	1

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				54	Energy/healthy supplement 2	1	1
55	Energy/healthy supplement 2	1	1
				56	Energy/healthy supplement 2	1	1
57	Energy/healthy supplement 2	1	1
				58	Energy/healthy supplement 2	1	1
59	Energy/healthy supplement 2	1	1
				60	Energy/healthy supplement 2	1	1
61	Energy/healthy supplement 2	1	1.5
				62	Energy/healthy supplement 2	0.5	1.5
63	The oral pain alleviating agent	0.54	0.5
				64	The oral pain alleviating agent	1.54	1
65	The oral pain alleviating agent	0.5	0.54
				66	The oral pain alleviating agent	1.54	1
67	The oral pain alleviating agent	1.04	1
				68	The oral pain alleviating agent	1.24	1.5
69	The oral pain alleviating agent	1.24	1.5
				70	The oral pain alleviating agent	1.24	1.5
71	The oral pain alleviating agent	1.24	1.5
				72	The oral pain alleviating agent	1.24	1.5
73	The oral pain alleviating agent	1.24	1.5
				74	Energy/healthy supplement 2	0.5	1.5
75	Melatonin	1	2
				76	Melatonin	1	2
77	Melatonin	1	2
				78	Melatonin	1	1.5
79	Melatonin	1.1	1.3
				80	Melatonin	1.2	1.3
81	Chlorine dioxide	1.5	1.5
				82	Multivitamin	1	1
83	Multivitamin	1	1
				84	Zinc/Ramulus Sambuci Williamsii	0.5	1
85	Energy/healthy supplement 2	0.75	1
				86	Energy/healthy supplement 2	0.75	1
87	Energy/healthy supplement 2	0.75	1
				88	Melatonin	1.1	1.3
89	Multivitamin	1	1
				90	Compound vitamin B	1	1
91	Multivitamin	1	1
				92	Compound vitamin B	1	1

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				93	Multivitamin	1	1
94	Multivitamin	1	1
				95	Energy/healthy supplement 2	0.75	1
96	Multivitamin	1	1
				97	Melatonin	1	1
98	Energy/healthy supplement 2	0.75	1
				99	Energy/healthy supplement 2	0.75	1
100	Energy/healthy supplement 2	0.75	1
				101	Energy/healthy supplement 2	1	1.5
102	Energy/healthy supplement 2	1	1.5
				103	Energy/healthy supplement 2	1	2
104	Energy/healthy supplement 2	1.5	1
				105	Energy/healthy supplement 2	1	2
106	Energy/healthy supplement 2	1	2
				107	Energy/healthy supplement 2	1	1.5
108	Energy/healthy supplement 2	1	2
				109	Energy/healthy supplement 2	1	1.5
110	Energy/healthy supplement 2	1	1.5
				111	Energy/healthy supplement 2	1	1.5
112	Energy/healthy supplement 2	1	1.5
				113	Energy/healthy supplement 2	1	1.5
114	Energy/healthy supplement 2	1	1.5
				115	Multivitamin	1	1.5
116	Multivitamin	1	1.5
				117	Immunostimulant	1	1
118	Melatonin	1.1	1.3
				119	Melatonin	1.1	1.3
120	Melatonin	1.1	1.3
				121	Melatonin	1.1	1.3
122	Melatonin	0.5	0.75
				123	Flu and cough medicine (COLD﹠COUGH)	1	1
124	Flu and cough medicine (COLD﹠COUGH)	1	1
				125	Multivitamin	1	1
126	Multivitamin	1	1
				127	Multivitamin	1	1.5
128	Multivitamin	1	1
				129	Multivitamin	1	1
130	Multivitamin	1	1.5
				131	Multivitamin	1	1

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				132	Multivitamin	1	1
133	Compound vitamin B	1	1
				134	Compound vitamin B	1	1
135	Compound vitamin B	1	1
				136	Compound vitamin B	1	1
137	Energy/healthy supplement 2	1.5	1.5
				138	Energy/healthy supplement 2	1.5	1.5
139	Energy/healthy supplement 2	1.5	1.5
				140	Multivitamin	1	1
141	Compound vitamin B	1	1
				142	Compound vitamin B	1	1
143	Multivitamin	1	1
				144	Compound vitamin B	1	1
145	Multivitamin	1	1
				146	Multivitamin	1	1
147	Multivitamin	1	1
				148	Multivitamin	1	1
149	Compound vitamin B	1	1
				150	Compound vitamin B	1	1
151	Multivitamin	1	1
				152	Multivitamin	1	1
153	Multivitamin	1	1
				154	Multivitamin	1.5	0.3
155	Energy/healthy supplement 2	1.5	1
				156	Energy/healthy supplement 2	1	1
157	Energy/healthy supplement 2	1	1
				158	Multivitamin	1	1
159	Multivitamin	1	1
				160	Multivitamin	1.5	0.3
161	Multivitamin	1	1
				162	Compound vitamin B	1	1
163	Compound vitamin B	1	1
				164	Energy/healthy supplement 2	0.5	0.5
165	Energy/healthy supplement 2	0.5	0.5
				166	Energy/healthy supplement 2	0.5	0.5
167	Energy/healthy supplement 2	0.5	0.5
				168	Energy/healthy supplement 2	0.5	0.5
169	Energy/healthy supplement 2	0.5	0.5
				170	Energy/healthy supplement 2	0.5	0.5

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				171	Energy/healthy supplement 2	1	0.5
172	Energy/healthy supplement 2	1	0.5
				173	Multivitamin	1	1
174	Multivitamin	1	1
				175	Energy/healthy supplement 2	0.5	0.5
176	Multivitamin	1	1
				177	Energy/healthy supplement 2	0.5	0.5
178	Energy/healthy supplement 2	0.5	0.5
				179	Multivitamin	1	1
180	Multivitamin	1	1
				181	Energy/healthy supplement 2	1	0.5
182	Energy/healthy supplement 2	1	0.5
				183	Multivitamin	1	1
184	Multivitamin	1	1
				185	Multivitamin	1	1
186	Multivitamin	1	1
				187	Multivitamin	1	1
188	Energy/healthy supplement 2	1	0.5
				189	Multivitamin	1	1
190	Multivitamin	1	1
				191	Multivitamin	1	1
192	Multivitamin	1	1
				193	Multivitamin	1.37	2.05
194	Multivitamin	1	1
				195	Multivitamin	1	1
196	Multivitamin	1	1
				197	Compound vitamin B	1	1
198	Energy/healthy supplement 2	1	0.5
				199	Energy/healthy supplement 2	1	0.5
200	Energy/healthy supplement 2	1	0.5
				201	Compound vitamin B	1	1
202	Multivitamin	1	1
				203	Multivitamin	1	1
204	Melatonin	1.1	1.3
				205	Multivitamin	1.5	0.3
206	Multivitamin	1	1
				207	The stress reduction agent	1	0.3
208	Multivitamin	1	1
				209	Multivitamin	1	1

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				210	Multivitamin	1	1
211	Energy/healthy supplement 2	1	0.5
				212	Energy/healthy supplement 2	1	0.5
213	Energy/healthy supplement 2	1	0.5
				214	Energy/healthy supplement 2	1	0.5
215	Energy/healthy supplement 2	1	0.5
				216	Multivitamin	1.5	0.3
217	Melatonin	1	0.5
				218	Melatonin	1	0.5
219	The stress reduction agent	1	0.3
				220	Multivitamin	1	1
221	Melatonin	1	0.5
				222	Multivitamin	1.5	0.3
223	Multivitamin	1	1
				224	Multivitamin	1	1
225	Cinnamnt	1	1
				226	Melatonin	1	0.5
227	Melatonin	1	0.5
				228	Compound vitamin B	1	1
229	Multivitamin	1	1
				230	Multivitamin	1	1
231	Multivitamin	1	1
				232	Multivitamin	1	1
233	Multivitamin	1	1
				234	Multivitamin	1	1
235	Multivitamin	1	1
				236	Multivitamin	1	1
237	Multivitamin	1	1
				238	Multivitamin	1	1
239	Multivitamin	1	1
				240	Multivitamin	1	1
241	Benzocaine/menthol	1.5	1.5
				242	Multivitamin	1	1
243	Dextromethorphan hydrobromide	0.5	1.82

¹Sipernat 500LS available from Degussa (Degussa)

²Any/all following activating agents or its combination that energy/healthy supplement can contain:

Green tea, brazilian cocoa, methylpyrrole chromium, caffeine, Yohimbine Hcl, taurine, vitamin B3, vitamin B6, vitamin B12

Except silicon dioxide and magnesium stearate, also contain various components such as polymer and flavoring agent etc. in every kind of film listing above.All the other components of the every kind of film that adopts in the table 2 are as described below.

The film that is defined as " sour agent " in the last table 2 contains the following component listed as table 3:

Table 3

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-60％
Citric acid	0.01％-40％
		Natural and synthetic flavoring agent	0.01％-25％
Arabic gum	0.01％-10％
		Magnesium stearate	0.01％-10％
Sodium hexameta phosphate	0.01％-5％
		Silicon dioxide	0.01％-2％
Polyoxyethylene sorbitan monoleate	0％-5％
		Malic acid	0.01％-10％
Aspartame	0.01％-3.5％
		Acesulfame potassium	0.01％-0.5％
Dyestuff	0.01％-1％
		Potassium sorbate	0.01％-0.1％
Sodium benzoate	0.01％-0.1％

The film that is defined as " benzocaine/menthol " in the last table 2 contains the following component listed as table 4:

Table 4

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-70％
Natural and synthetic flavoring agent	0.01％-25％
		Poly(ethylene oxide)	0.01％-50％
The menthol crystal	0.01％-30％
		Corn starch	0.01％-30％
Benzocaine	0.01％-10％
		Sucralose	0.01％-5％
Malic acid	0.01％-5％
		Magnesium stearate	0.01％-10％
Silicon dioxide	0.01％-2％
		Titanium dioxide	0.01％-5％
Butylated hydroxy-methylbenzene	0.01％-1％
		Dyestuff	0.01％-1％

The film that is defined as " energy/healthy supplement " in the last table 2 contains the following component listed as table 5:

Table 5

Component	Weight %
		Hydroxypropyl emthylcellulose	0％-70％％
Hydroxypropyl cellulose	0％-40％
		Pectin	0％-40％
Natural and synthetic flavoring agent/seasoning adjuvant	0％-30％
		Dextrosan	0.01％-30％
Sodium carboxymethyl cellulose	0％-10％
		Energy/healthy activating agent 2	0.01％-50％
Erithritol	0％-20％
		Sucralose	0.01％-5％
Citric acid	0％-10％
		Magnesium stearate	0.01％-10％
Glyceryl monooleate	0％-1％
		Silicon dioxide	0.01％-2％
Polyoxyethylene sorbitan monoleate	0％-1％
		The sorbitan monoleate	0％-1％
Potassium sorbate	0％-0.1％
		Sodium benzoate	0％-0.1％
Sodium hexameta phosphate	0％-10％
		Propylene glycol	0％-25％
Arabic gum	0％-10％
		Dyestuff	0.01％-1％

The film that is defined as " oral pain alleviating agent " in the last table 2 contains the following component listed as table 6:

Table 6

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-70％
Choline salicylate	0.01％-60％
		Natural and synthetic flavoring agent	0.01％-10％
Magnesium stearate	0.01-5％

Silicon dioxide	0.01-2％
		Cetalkonium chloride	0.01％-5％
Methyl parahydroxybenzoate	0.01％-0.1％
		Dimethyl polysiloxane	0.01％-0.05％

The film that is defined as " melatonin " in the last table 2 contains the following component listed as table 7:

Table 7

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-70％
Natural and synthetic flavoring agent/seasoning adjuvant	0.01％-20％
		Poly(ethylene oxide)	0.01％-30％
Melatonin	0.01％-20％
		Pectin	0.01％-10％
Dextrosan	0.01％-20％
		Sucralose	0.01％-5％
Magnesium stearate	0.01％-10％
		Silicon dioxide	0.01％-2％
Glyceryl monooleate	0.01％-1％
		Titanium dioxide	0.01％-5％
Monoammonium glycyrrhizinate	0.01％-2％
		Butylated hydroxy-methylbenzene	0.01％-1％
Dyestuff	0.01％-1％

The film that is defined as " chlorine dioxide " in the last table 2 contains the following component listed as table 8:

Table 8

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-70％
Poly(ethylene oxide)	0.01％-50％
		Dextrosan	0.01％-20％
Natural and synthetic flavoring agent/seasoning adjuvant	0.01％-30％
		Magnesium stearate	0.01％-5％

Silicon dioxide	0.01％-2％
		Sucralose	0.01％-5％
The zinc gluconate dihydrate	0.01％-5％
		Citric acid	0.01％-2％
Glyceryl monooleate	0.01％-1％
		Sodium hydroxide	0.01％-5％
Sodium bicarbonate	0.01％-5％
		2% ClO 2 solution	0.01％-10％
Butylated hydroxy-methylbenzene	0.01％-1％
		Dyestuff	0.01％-1％
Sodium benzoate	0.01％-0.1％

The film that is defined as " multivitamin " in the last table 2 contains the following component listed as table 9:

Table 9

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-50％
Natural and synthetic flavoring agent	0.01％-20％
		Nicotiamide-100% (vitamin B3)	0.01％-30％
Poly(ethylene oxide)	0.01％-30％
		Dextrosan	0.01％-20％
Ascorbic acid-100% (vitamin C)	0.01％-20％
		50% alpha-tocopherol acetate-91.2%	0.01％-10％
Dextro calcium pantothenate-92% (vitamin B5)	0.01％-10％
		Sucralose	0.01％-5％
Palimitate-A-15%	0.01％-10％
		Hydrochloric acid pyrrole-82.3% (vitamin B6) of trembling	0.01％-10％
Riboflavin-100% (vitamin B2)	0.01％-10％
		Thiamine hydrochloride-89.2% (vitamin B 1)	0.01％-10％
Magnesium stearate	0.01％-2％
		Silicon dioxide	0.01％-2％

Glyceryl monooleate	0.01％-1％
		5% phytomenadione 00%	0.01％-5％
2.5% vitamin D3 liquid-100%	0.01％-5％
		Butylated hydroxy-methylbenzene	0.01％-1％
Cyanogen cobalt vitamin-100% (vitamin B12)	0.001％-1％

The film that is defined as " zinc/Ramulus Sambuci Williamsii " in the last table 2 contains the following component listed as table 10:

Table 10

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-60％
Zinc gluconate	0.01％-20％
		The fruit of Ramulus Sambuci Williamsii extract	0.01％-20％
Fructose	0.01％-20％
		Natural and synthetic flavoring agent	0.01％-30％
Poly(ethylene oxide)	0.01％-20％
		Dextrosan	0.01％-20％
Ascorbic acid-100% (vitamin C)	0.01％-20％
		Sucralose	0.01％-5％
Glyceryl monooleate	0.01％-1％
		Magnesium stearate	0.01％-5％
Titanium dioxide	0.01％-2％
		Silicon dioxide	0.01％-2％
Butylated hydroxy-methylbenzene	0.01％-1％

The film that is defined as " compound vitamin B " in the last table 2 contains the following component listed as table 11:

Table 11

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-60％
Poly(ethylene oxide)	0.01％-50％
		Dextro calcium pantothenate-92% (vitamin B5)	0.01％-20％
Dextrosan	0.01％-30％

Natural and synthetic flavoring agent/seasoning adjuvant	0.01％-25％
		Hydrochloric acid pyrrole-82.3% (vitamin B6) of trembling	0.01％-20％
Riboflavin-100% (vitamin B2)	0.01％-20％
		Thiamine hydrochloride-89.2% (vitamin B1)	0.01％-20％
Sucralose	0.01％-5％
		Propylene glycol	0.01％-5％
Magnesium stearate	0.01％-10％
		Silicon dioxide	0.01％-2％
Glyceryl monooleate	0.01％-1％
		Butylated hydroxy-methylbenzene	0.01％-1％
Dyestuff	0.01％-1％
		Cyanogen cobalt vitamin-100% (vitamin B12)	0.001％-1％

The film that is defined as " immunostimulant " in the last table 2 contains the following component listed as table 12:

Table 12

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-70％
Dextrosan	0.01％-50％
		Poly(ethylene oxide)	0.01％-50％
Zinc citrate trihydrate.	0.01％-40％
		Sucralose	0.01％-5％
Natural flavouring	0.01％-20％
		Citric acid	0.01％-20％
Magnesium stearate	0.01％-10％
		Silicon dioxide	0.01％-2％
Sodium citrate	0.01％-5％
		Glyceryl monooleate	0.01％-1％
Butylated hydroxy-methylbenzene	0.01％-2％
		Monoammonium glycyrrhizinate	0.01％-1％
Dyestuff	0.01％-1％

The film that is defined as " flu and cough medicine " in the last table 2 contains the following component listed as table 13:

Table 13

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-60％
Dextrosan	0.01％-30％
		Natural and synthetic flavoring agent	0.01％-25％
Poly(ethylene oxide)	0.01％-50％
		Ascorbic acid-100% (vitamin C)	0.01％-30％
The zinc citrate dihydrate	0.01％-20％
		Echinacea extract (ECHINACEA PURPUREA)	0.01％-20％
Sucralose	0.01％-10％
		Pectin	0.01％-20％
Citric acid	0.01％-10％
		Sodium citrate	0.01％-5％
Magnesium stearate	0.01％-10％
		Silicon dioxide	0.01％-2％
Glyceryl monooleate	0.01％-1％
		Dyestuff	0.01％-1％
Butylated hydroxy-methylbenzene	0.01％-1％
		Monoammonium glycyrrhizinate	0.01％-1％

The film that is defined as " stress reduction agent " in the last table 2 contains the following component listed as table 14:

Table 14

Component	Weight %
		Hydroxypropyl emthylcellulose	0.01％-60％
Flos Chrysanthemi	0.01％-40％
		Herba Passiflorae Caeruleae	0.01％-40％
Pectin	0.01％-20％
		Natural and synthetic flavoring agent	0.01％-25％
Glycerol	0.01％-10％

Polyoxyethylene sorbitan monoleate	0％-2％
		Sucralose	0.01％-5％
Polydimethylsiloxane Emulsion	0.01％-2％
		Aspartame	0.01％-5％
Acesulfame potassium	0.01％-3％
		Potassium sorbate	0.01％-1％

The film that is defined as " cinnamnt " in the last table 2 contains the following component listed as table 15:

Table 15

Form	Weight %
		Hydroxypropyl emthylcellulose	0.01％-70％
Poly(ethylene oxide)	0.01％-50％
		Dextrosan	0.01％-30％
Butylated hydroxy-methylbenzene	0.01％-1％
		Glyceryl monooleate	0.01％-1％
Magnesium stearate	0.01％-10％
		Silicon dioxide	0.01％-2％
Potassium sorbate	0.01％-0.1％
		Sodium benzoate	0.01％-0.1％
Natural and synthetic flavoring agent	0.01％-30％
		Sucralose	0.01％-5％
Xylitol	0.01％-10％
		Dyestuff	0.01％-1％

The film that is defined as " dextromethorphan hydrobromide " in the last table 2 contains the following component listed as table 16:

Table 16

Component	Weight %
		Dextromethorphan hydrobromide 60%	0.01％-60％
Poly(ethylene oxide)	0.01％-70％
		Dextrosan	0.01％-30％
Hydroxypropyl emthylcellulose	0.01％-70％

Natural and synthetic flavoring agent	0.01％-30％
		Sucralose	0.01％-5％
Magnesium stearate	0.01％-10％
		Silicon dioxide	0％-2％
Sodium bicarbonate	0.01％-5％
		Xanthan gum	0.01％-10％
Titanium dioxide	0.01％-5％
		Butylated hydroxy-methylbenzene	0.01％-1％
Dyestuff	0.01％-1％

The film for preparing among these embodiment has the fluidizer characteristic of improvement, especially has the ability of adhesion ground slip to each other.

Embodiment 244-300:

Be combined with as the silicon dioxide of antiplastering aid and the water-soluble film of magnesium stearate with the described content preparation of table 17.More specifically say, as shown in the table, various silicon dioxide and magnesium stearate combination are mixed in the various film composition.

Table 17

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				244	Acid agent (SOURS)	1.5	2.5
245	Energy/healthy supplement 2	0.75	1
				246	Energy/healthy supplement 2	0.75	1
247	Melatonin	1	2
				248	Melatonin	1.5	1.5
249	Chlorine dioxide	1.5	1.5
				250	Melatonin	1.5	1.5
251	Melatonin	1.5	1.5
				252	Melatonin	1.5	1.5
253	Melatonin	1.5	1.5
				254	Chlorine dioxide	1.5	1.5
255	Melatonin	1.1	1.3
				256	Multivitamin	1	1
257	Multivitamin	1	1
				258	Compound vitamin B	1	1
259	Multivitamin	1	1
				260	Compound vitamin B	1	1

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				261	Flu and cough medicine (COLD﹠COUGH)	1	1
262	Multivitamin	1	1
				263	Multivitamin	1	1
264	Multivitamin	1	1
				265	Multivitamin
266	Multivitamin
				267	Multivitamin
268	Multivitamin	1	1.5
				269	Immunostimulant	1.16	1.16
270	Multivitamin	1	1
				271	Energy/healthy supplement 2	1	1.5
272	Multivitamin	1	1.5
				273	Multivitamin	1	1.5
274	Melatonin	1.1	1.3
				275	Multivitamin	1	1
276	Multivitamin	1	1
				277	Multivitamin	1	1
278	Multivitamin	1	1
				279	Multivitamin	1	1
280	Energy/healthy supplement 2	1.5	1.5
				281	Multivitamin	1	1.5
282	Multivitamin	1	1.5
				283	Multivitamin	1.5	0.3
284	Multivitamin	1	1
				285	Compound vitamin B	1	1
286	Energy/healthy supplement 2	1	0.5
				287	Multivitamin	1	1
288	Melatonin	1.1	1.3
				289	Compound vitamin B	1	1
290	Compound vitamin B	1	1
				291	Energy/healthy supplement 2	1	0.5
292	Energy/healthy supplement 2	1	0.5
				293	Compound vitamin B	1	1
294	Multivitamin	1	1
				295	Chlorine dioxide	1.5	1.5
296	Multivitamin	1	1.5
				297	Multivitamin	1	1
298	Multivitamin	1	1

Embodiment	The kind of film	Silicon dioxide 1(weight %)	Magnesium stearate (weight %)
				299	Multivitamin	1	1
300	Benzocaine/menthol	1.5	1.5

¹Sipernat 500LS available from Degussa (Degussa)

²Any/all following activating agents or its combination that energy/healthy supplement can contain:

Green tea, brazilian cocoa, methylpyrrole chromium, caffeine, Yohimbine Hcl, taurine, vitamin B3, vitamin B6, vitamin B12 are except silicon dioxide and magnesium stearate, and be relevant with last table 2 as contained all the other components in the listed film of table 17.

Table 2 is identical with the kind of 17 films that adopt.

The film for preparing among these embodiment has the fluidizer characteristic of improvement, especially has the ability of adhesion ground slip to each other.

Think the preferred embodiment of the present invention at present although described, but those skilled in the art will recognize that, can make a change and modify it when not deviating from the present invention's spirit, the present invention be intended to comprise that all these classes change and modification, and it is fallen within the true scope of the present invention.

Claims (26)

1. edible film that is used for active agent delivery comprises:

The edible water-soluble polymer;

At least a antiplastering aid, it is selected from lubricant, antitack agent, fluidizer and combination thereof; With

Active component, it is selected from enamel, medicament, vitamin, bioactivator and combination thereof,

Wherein said film is a self-supporting.

2. film as claimed in claim 1 is characterized in that described antiplastering aid comprises vitamin E TPGS.

3. film as claimed in claim 1 is characterized in that described antiplastering aid comprises magnesium stearate.

4. film as claimed in claim 3 is characterized in that described antiplastering aid also comprises silicon dioxide.

5. film as claimed in claim 1 is characterized in that the content of described antiplastering aid accounts for the 0.01-20% of described delivery system weight.

6. film as claimed in claim 1 is characterized in that, described antiplastering aid comprises:

Content accounts for the magnesium stearate of the 0.1-2.5% of described delivery system weight; With

Content accounts for the silicon dioxide of the 0.1-1.5% of described delivery system weight.

7. film as claimed in claim 1 is characterized in that described water-soluble polymer comprises poly(ethylene oxide) and cellulosic polymer.

8. film as claimed in claim 7 is characterized in that described cellulosic polymer comprises hydroxypropyl cellulose.

9. film as claimed in claim 7 is characterized in that described cellulosic polymer comprises hydroxypropyl emthylcellulose.

10. film as claimed in claim 1 is characterized in that described active component comprises dextromethorphan.

11. film as claimed in claim 1 is characterized in that, also comprises dextrosan.

12. film as claimed in claim 1 is characterized in that, described film is used for mammiferous oral cavity.

13. film as claimed in claim 13 is characterized in that, described film adheres to mammiferous tongue.

14. the edible film of an active agent delivery comprises:

The edible water-soluble polymers compositions, it contains at least a hydroxypropyl cellulose, hydroxypropyl emthylcellulose, poly(ethylene oxide) and the combination of polymers thereof of being selected from;

Active component, it is selected from enamel, medicament, vitamin, bioactivator and combination thereof; With

Antiplastering aid, it contains the vitamin E TPGS that content accounts for described film weight 0.01-20%.

15. an edible film that is used for active agent delivery comprises:

The edible water-soluble polymers compositions, it contains poly(ethylene oxide) and is selected from hydroxypropyl cellulose, hydroxypropyl emthylcellulose and combination of polymers thereof; With

Vitamin E TPGS, its content are enough to provide resistance to bond and treatment characteristic,

Wherein said film is a self-supporting.

16. an edible film that is used for active agent delivery comprises:

The edible water-soluble polymer, it contains poly(ethylene oxide) and hydroxypropyl cellulose;

Dextrosan, the ratio of wherein said poly(ethylene oxide), hydroxypropyl cellulose and dextrosan is about 45: 45: 10;

Active component, it is selected from enamel, medicament, vitamin, bioactivator and combination thereof; With

At least a antiplastering aid.

17. an edible film that is used for active agent delivery comprises:

(a) self-supporting film, it has at least one surface, and described film comprises:

(i) edible water-soluble polymer; With

(ii) active component, it is selected from enamel, medicament, vitamin, bioactivator and combination thereof; With

(b) coating, it covers at least one surface of described self-supporting film, and described coating contains at least a antiplastering aid.

18. a multilayer film that is used for active agent delivery comprises:

(a) at least a first rete, it comprises:

(i) edible water-soluble polymer; With

(ii) antiplastering aid; With

(b) second rete, it comprises:

(i) edible water-soluble polymer; With

(ii) active component, it is selected from enamel, medicament, vitamin, bioactivator and combination thereof,

Wherein said first rete contacts with described second rete basically.

19. multilayer film as claimed in claim 18 is characterized in that, described first rete is laminated on described second rete.

20. one kind prepares and has the method for the self-supporting film of equally distributed component basically, comprising:

(a) with the edible water-soluble polymer, solvent, the active component and at least a antiplastering aid that are selected from enamel, medicament, vitamin, bioactivator and combination thereof mix, and form the substrate that is evenly distributed with described component;

(b) form the self-supporting film by described substrate;

(c) provide surface with end face and bottom surface;

(d) described film is transported on the described end face on described surface; With

(e) the described bottom surface heating to described surface makes the film drying.

21. method as claimed in claim 20 is characterized in that, described antiplastering aid comprises vitamin E TPGS.

22. method as claimed in claim 20 is characterized in that, described antiplastering aid comprises magnesium stearate and silicon dioxide.

23. method as claimed in claim 20 is characterized in that, described substrate also contains dextrosan.

24. method as claimed in claim 20 is characterized in that, described film can absorb.

25. method as claimed in claim 20 is characterized in that, and is flexible when described film is dry.

26. method as claimed in claim 20 is characterized in that, described step (e) comprises that the described bottom surface to described surface applies thermal current, and does not apply the end face air-flow basically.

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