CN1997331A - Pharmaceutical tablets with separation marking on one side thereof - Google Patents

Abstract

A pharmaceutical tablet having two segments, one of which is a top segment and the other of which is a bottom segment, said tablet having at least one side wherein said tablet is provided with a separation mark or marks.

Description

The tablet that on the tablet one side, contains separation marking

Technical field

The invention describes in novel mode and contain underlined segmentation tablet in tablet or on the tablet, labelling is preferably placed in the fragment (segment) so that carry out in a fragment optional required the cutting apart directly of described tablet, cuts apart thereby help to produce more accurate tablet.

Background of invention

For a long time for tablet provides indentation, it is the continuous indenture that passes the tablet surface.The purposes of indentation be identified for described tablet cut apart (segmentation) become two less subunits (being known as tablettes in this article) may with the position of needs.

The problem of the existing form of indentation (scored) sheet is known.These problems comprise that the loss of active medicine and the inaccuracy of tablet cut apart, and the tablet of therefore planning to be divided into two five equilibriums does not reach this ideal state usually.

Therefore, long-recognized is even indentation is arranged, also to be difficult to accurate Dividable tablet.

Many medicines need dosage to regulate, warfarin (warfarin) for example, and its scored tablet is often separated.These dosage that undertaken by patient's Dividable tablet are regulated and have been confirmed to be is coarse.As described below, for many years, the expert appeals that always pharmaceuticals industry improves the quality that tablet is cut apart, but does not all reach optimum efficiency before the present invention.

In 1984, people such as Stimpel (" Stimpel ") described the relative accuracy that the various tablets of treatment cardiovascular problems are cut apart.People such as M.Stimpel, " Breaking Tablets inHalf " The Lancet (1984): 1299.Carry out although cut apart by seasoned handyman, Stimpel finds to cut apart and inaccuracy, and thinks that patient's actual use can produce more not satisfied result.Stimpel appeals that pharmaceuticals industry improves the accuracy of Dividable tablet: " any obviously is wrong about tablet can not be caused the imagination of inaccuracy dosage in two.This potential origin cause of formation of inexactness is serious more (our research is carried out under ideal conditions) in clinical condition, pharmaceuticals industry should be by improving severability (as to metoprolol and logroton) or better, by selling more kinds of no incising tablets, address the above problem thus so that all dosage that may use in clinical to be provided.”

Although this discovery and statement are arranged, although and issued about optimizing the various patents of indentation pattern and/or pill shapes, people such as Rodenhuis (2004) point out: " mechanism of action that improves line with forbid that this dosage form is compared be more practical mode " (adding heavy label).People such as N.Rodenhuis, " The rationale of scored tablets as dosage form. " European J.of Pharmaceutical Sciences 21 (2004): 305-308 (hereinafter being called " Rodenhuis ").Rodenhuis observed, and European regulator came into effect the policy of restriction tablet indentation in 1998.According to the saying of Rodenhuis, this policy changes may be relevant with following situation: " about the many recent report of the line of poor performance ", " many scored tablets are difficult to cut apart " " two halves that many scored tablets are subdivided into show not satisfied quality homogeneity ".The author has then described the useful aspect of scored tablet subsequently.Comprehensive review article for this topic, referring to van Santen, E., Barends, D.M. and Frijlink, H.W. " Breaking ofscored tablets:a review. " European J.of Pharmaceutics andBiopharmaceutics 53 (2002): 139-145.

Some researchs of current this problem severity of confirmation are described below.

People such as Peek, (2002) have been studied the tablet that " the aged patient " in 50-79 year implement and have been cut apart.Peek, B.T., Al-Achi, A., and Coombs, S.J. " Accuracy of Tablet Splittingby Elderly Patients. " The Journal of the American Medical Association 288No.4 (2002): 139-145.Under the situation that does not have concrete indication, cut apart scored tablet with mechanical tablet cutter and cause extremely not satisfied tablet to separate.For example, warfarin on average is divided into 1.9 and 3.1 milligrams of tablets for 5 milligrams.This effective anticoagulant has so narrow therapeutic domain so that has made 2,2.5 and 3 milligrams of tablet amounts.People such as Biron (1999) confirm that warfarin also often is divided into less than 4.25 milligrams or greater than 5.75 milligrams for 10 milligrams.Biron, C., Liczner, P, Hansel, S. and Schved, J.F., " Oral Anticoagulant Drugs:Do NotCut Tablets in Quarters. " Thromb Haemost 1201 (1999).In addition, they confirm that the mass loss that is caused by cracked (crumbling), chipping or the destruction (breaking) of warfarin tablet is tangible on statistics.They confirm that also the quartering of tablet is inaccuracy very.

People such as McDevitt (1998) find, 25 milligrams not the craft of indentation Hydrochlorothiazide (HCTZ) tablet cut apart and be on duty mutually so that 12.4% depart from ideal weight more than 20%.McDevitt, J.T., Gurst, A.H., and Chen, Y. " Accuracy of Tablet Splitting. " Pharmacotherapy 18 No.1 (1998): 193-197.77% tested object claims that they would rather also be unwilling to cut apart not 25 milligrams of tablets of indentation for 12.5 milligrams of more expenses of tablet payment of HCTZ of making separately.

People such as Rosenberg (2002) have studied the Dividable tablet that the pharmacists tells.Rosenberg, J.M., Nathan, J.P., and Plakogiannis, F. " Weight Variability of Pharmacist-Dispensed Split Tablets. " Journal of American Pharmaceutical Association42 No.2 (2002): 200-205.They find " tablet cut apart cause too high weight differential incidence rate ".They advise " should develop the standard of the isotropism of guaranteeing Dividable tablet ".

People such as Teng (2002), in laboratory is provided with trained personnel's Dividable tablet, " we have tested the major part in 11 medicines; when they are divided into the ability of the two halves tablet that dosage equates when evaluation; by the test of liberally interpreted USP (American Pharmacopeia; United States Pharmacopeia) isotropism ... be the practice of saving cost or improving the dosage regimen Dividable tablet ... do not recommend the patient who uses the medicine with bigger toxicity and precipitous dose response efficacy profile " Teng reaches a conclusion and is, J., Song, C.K., Williams, R.L., and Polli, J.E. " Lack of Mdication Dose Uniformity in Commonly Split Tablets. " Journal of American Pharmaceutical Association 42 No.2 (2002): 195-199.

Rodenhuis proposes, and in a research of Holland, 31% was segmented before swallowing in all tablets.In the U.S., many " health care " insurance institution encourages the patient to cut apart the not irregularly shaped tablet of indentation.In the U.S., although many tablets all do not have indentation or can provide with capsule form by tabletting.The present invention for indentation and not incising tablet solution is provided, it has solved the problems referred to above better.

In addition, it is common in the pharmaceuticals treating with combination product, this means that a dosage form can contain more than one active component.This therapeutic modality is can part as described below:

Association area of the present invention is the composition of medicine treatment field that is used for systemic arterial hypertension (" hypertension ").Technical, hypertensive combined therapy relates on conventional basis and to use the hypertension of two or more medicines with the treatment patient.Usually, this term means that carrying out every day with at least two kinds of medicines treats.

It is existing for a long time that combined therapy is used for the treatment of hypertension.Generally infer, under maximal allowance dose, only about half of can not the treatment at blood pressure in all hypertension cases with a kind of medicine.For auxiliary treatment, be formed in the solid oral dosage form that comprises multiple actives in a tablet or the capsule.These dosage forms are known as " fixed dosage " combination product, because patient, nurse or pharmacists method that activating agent is not separated from one another.Sica (2002) claims: " there is tradition quite of a specified duration in combined therapy; trace back to the fifties in last century " is in the back of same piece of writing article, the author spells out the shortcoming of using the fixed dosage method, embodiment of the present invention provide novel and effective solution (Sica for this shortcoming, D., Drugs, 2002; 62 (3)): " shortcoming of using the fixed dosage combination is that every kind of component lacks the dosed administration motility, uses the inherent dosed administration motility of independent assortment although the doctor seldom farthest utilizes " Rationale for Fixed-Dose Combinations in the Treatment ofHypertension: ".Use the fixed dosage combined therapy, if the amount of need the condition of looking regulating arbitrary medicine for BP control just needs independent prescription.This has improved the complexity of dosage regimen and may have negative effect to compliance (compliance).In addition, the fixed dosage combined therapy can not provide is enough to treat usually and the medication amount of hypertension and the pharyngalgia of depositing or congestive heart failure and so on disease.”

(it helps with novel mode Dividable tablet segmentation, the layering tablet of the present invention by being described in wherein or having on it novel markings position, labelling is preferably placed in a fragment or one deck but not runs through all fragments or layer as in the present practice of layering tablet), the method for improving above-mentioned condition is provided.

In the high speed manufacture process, it is infeasible technically only in the intermediate layer of three layers of tablet indentation to be set, and requires tablet die head (die) to have the counterpart of the thing that is known as embossing on punch press because do like this.When in described die head, forming tablet, in fact produce and have the tablet that begins horizontally extending structure from the die head of recessed tablet, but it can not be released from described die head subsequently, does like this and can destroy tablet, and the physics that the release of its underpart can be subjected to described " embossing " hinders.

Except top and bottom indentation, knownly make vertical indentation sometimes, it extends on the tablet height, is produced by " embossing " as a tablet die head part.The example of the tablet of so making is Desyrel Dividose , its have by backform dash and bottom punch on the indentation made in a conventional manner of embossing, and the vertical indentation that in tablet height (being minor axis in this case), extends, " embossing " that this vertical indentation produces from die head.

In addition, also be not disclosed as the alternate manner that people indicate cut zone, this cut zone preferably is limited in one deck (fragment) of two-layer or multilamellar tablet.This possible mode comprises with edible oil ink print, gelatin band envelope (banding) and perforation.

Auxiliary prior art is provided is example with the product of commodity Norgesic  by name and Norgesic Forte  in order to cut apart the multilamellar tablet.This three drug products are made into three layers, and one deck only is made of aspirin, and one deck only is made of caffeine, and another layer only is made of orphenadrine citrate (orphenadrine citrate).The top layer that is provided (or bottom) indentation is limited to described layer very shallowly, and is positioned at the center of described layer.By indentation in a conventional manner Dividable tablet make and significantly be intended that all three layers of tablet all fracture trilaminar each layer all is divided into two halves.Before the present invention, also do not mention the supplementary means that makes breakaway poing be positioned at the intermediate layer of this three layers of tablet is provided, thereby make this tablet is cut apart to provide two than tabloid (" tablettes "), one contains whole top layer and a part of intermediate layer, and one contains bottom and a part of intermediate layer.

In addition, the present invention adopts layer painted so that tablet only passes the interface disconnection between a fragment or the fragment.Although it is known containing the tablet of different colours layer, also not their is not shaped or does not propose also that following use---the layering tablet can pass one deck but not all layers disconnection.

Summary of the invention

The invention provides and comprise two segmental tablets, one of them is the top fragment, and another is the bottom fragment, and described tablet has the surface that contacts with the inner surface (wall) of tablet die head (suppressing described tablet therein), and described tablet of the present invention contains:

(a) indentation on one side, wherein said indentation are not vertical orientated and the preferred levels orientation; (vertical and horizontal alignment can be determined according to the disclosure)

(b) mark of the position of the predetermined cut zone of the definite described tablet at least simultaneously;

(c) be positioned on the fragment or be positioned at two fragments band at the interface; Or

(d) sandwich layer of described tablet, wherein the first below fragment has identical color with the second top fragment and comprises the same medicine of pharmacologically effective dose or all lack any medicine of pharmacologically effective dose, with the 3rd inner fragment of inserting, it has and the different color of described first fragment, and it contains and the identical medicine of described first fragment when described first fragment contains the medicine of pharmacologically effective dose, or when described first fragment lacked any medicine of pharmacologically effective dose, it did not contain the medicine of any pharmacologically effective dose.

The correct position of separation marking is at the interface segmental at two.

Preferred tablet of the present invention is the tablet that separation marking is arranged in the individual chip that is not epimere or hypomere.

The present invention also is included in the tablet that contains at least one additional separation marking in one or more fragments as epimere or hypomere.

Therefore, main purpose of the present invention provides a zone of location tablet and causes passing the separation marking that the part fragment is cut apart.

The present invention also aims to provide following separation marking---it provides indication to pass the fragment Dividable tablet of relative non-activity.

Purpose of the present invention provides following Dividable tablet to produce the improved method of tablet part (parts) in addition---by the tablet that contains relative non-activity part being provided and indicating the tablet divider to apply power, thereby improve the mode of cutting apart accuracy of indentation and no incising tablet so that this tablet passes the part fracture of this relative non-activity of tablet.

According to this description, these and other objects of the present invention become apparent.

Description of drawings

Fig. 1 a is when impressed tablet face is watched, the cross section of the tablet of height greater than width;

Fig. 1 b is when the tablet face of indentation end is watched, the cross section of the tablet of Fig. 1 a;

Fig. 2 a-d is respectively when by the indentation separate tablet, the view of Fig. 1 a and Fig. 1 b;

Fig. 3 is the cross section that contains the tablet of two segmental height greater than width, and one of them fragment is about 4/3 of a tablet length;

Fig. 4 a-b is when the roughly center of tablet separates tablet, the view of Fig. 3;

Fig. 5 is the cross section that contains the tablet of 5 segmental height greater than width;

Fig. 6 a-b has passed a fragment when tablet is separated, the view of Fig. 5;

Fig. 7 a-c is that tablet has divided two steps (Dividable tablet is at first cut apart the tablette of Fig. 6 b then) to pass two fragments effectively when separating, the view of Fig. 5;

Fig. 8 is the perspective view of scored tablet of the present invention;

Fig. 9 is band envelope (banded) capsular front view of the present invention;

Figure 10 is the front view that the tablet of perforation is arranged from the teeth outwards according to the present invention; And

Figure 11 is the front view that the tablet of two printing dotted lines is arranged from the teeth outwards according to the present invention.

The specific embodiment

As in traditional scored tablet, separation marking itself just hints to apply cuts apart power so that disconnect at the separation marking place.Yet, be desirably in to utilize and can comprise in pharmaceutical packing of the present invention or the label and explicitly call for the written instruction of noting separation marking.

Term " fragment " is used to describe tablet of the present invention in this article.Fragment is represented the whole basic neighboring region uniformly of tablet of the present invention or tablette (seeing below).Fragment is made of one or more layers.The die head (just having carried out " filler ") that enters tablet machine fully at particulate matter is cambium layer afterwards.In compressed tablet as main topic of the present invention, no matter described particulate matter packless, tamp still fully compacting, all be considered as existing one deck.Can use twice or repeatedly continuous feed of basic identical particulate matter when forming tablet, with essentially identical when laminated together on these two kinds of compositions, they are regarded as a unit of tablet usually.Should " unit " be known as fragment, more specifically be called compound (compound) fragment.If described layer be successive (not cutting apart) and not with essentially identical layer adjacency, then fragment comprises one deck; This fragment is known as simple fragment at this.Essentially identical layer of fragment that constitutes by the multilamellar adjacency is known as compound fragment at this.

When using with tablet, term used herein " parallel " (" laterally ") and " vertical " are based on tablet when making in die head and make the back but break away from or release die head before spatial orientation.Thus, the top layer of tablet (fragment) is considered in internal layer and bottom (fragment) top.The layer and the fragment of tablet are considered to orthogonal placement, because granule vertically enters and cambium layer.

Tablet height representative vertical dimension from the least significant end of tablet to most significant end.Pass the wideest part intercepting tablet cross section of tablet, record two transverse dimensions.Unless the cross section of tablet is circular or square (not considering the inclined-plane or the cupping at square cross-sectional shape edge), otherwise at least two different transverse dimensions are arranged.Described two transverse dimensions are bigger is called width, the less degree of depth that is called.Tablet of the present invention comprises at least two fragments, has the release characteristics (just not having controlled release or " drug conveying " coating, additive or characteristic) of rapid release, and height greater than width.Tablet of the present invention does not use cement, glue, binding agent or analog to form.

When the concentration ratio of the contained active medicine of fragment contains another fragment of described medicine when rare, or when the concentration of a fragment contained drug is the maximum concentration of medicine described in all fragments of tablet when (this moment bigger the accuracy of separation more useful), the size or the separation marking that more need to limit separation marking will point to zone limited further on scope, so tablet is cut apart and can be carried out in the most desirable position of tablet.

The main isolating construction of making by Dividable tablet of the present invention is known as tablettes in this article, and in preferred embodiments, they contain one or more medicines of accurate amount.

The example of separation marking comprises: (a) indentation that has any desired contour type on one or more surfaces of tablet, for example triangle or square; (b) the printing mark of predetermined cut zone, for example solid line or dotted line on tablet; (c) " cut apart " or the printing mark of " cutting apart " and so on the symbol that it is cut apart with or without symbol, for example shears, arrow or round dot or series of discontinuous dots at this as marked graph, word; (d) to emphasize that still the pattern with suitable of form of straight lines setting is passed the indenture of the transverse dimensions of tablet; (e) band is for example around band whole or the part tablet, for example gelatin band or edible condensation zone; (f) pass the perforation of tablet, its can but be not limited to following making---machinery is removed a part of tablet to 0.1 to 0.5 millimeter the degree of depth, or with laser with effective wavelength and power to remove the material of pre-metering, these perforation can be with suitable arranged in patterns; (f) novel color indication, it for example forms by the contrast color of differential staining or uncoloured relative inactive segments, the white of the basic non-activity of this fragment top adjacency or coloured fragment and below are in abutting connection with white or coloured fragment of another basic non-activity, thereby the fragment of this relative non-activity can be identified as the center of the relative non-viable regions of tablet, and not need to print or indentation or need in the multilamellar tablet machine, not be molded into narrow contrast fragment (using one or more comparative particles therein) in the tablet to be formed for determining the contrast thin slice section of tablet cut zone position.

All these helps to determine the position of required cut zone, and the physics performance when helping to cut apart as required tablet of the present invention.Thus, preferred separation marking is the indentation that level is passed the interior segments of three fragment tablets, and wherein said interior segments lacks any medicine of pharmacologically active amount, and two outsides (top and bottom) fragment comprises the identical or different medicine of pharmacologically active amount.

The indentation of the above-mentioned type can not be made in commercial tablet is made, because do level " dividing plate (shelf) " or " embossing " of requirement in die head like this, this can form tablet but can hinder formed tablet and release from die head.But this indentation can for example use file or pass through the high speed autofrettage by hand by the alternate manner manufacturing.The various methods that apply mark, for example pharmaceutically acceptable printing ink and band envelope (banding) material are known and can be applied to the position that tablet is simultaneously gone up may need the zone of Dividable tablet with definite, for example pass the relative inactive segments that is clipped between two fragments and cut apart.

Width of nick is about 0.5 millimeter to about 3 millimeters, but should not surpass about 40-50% of tablet thickness.The length of separation marking is inessential, under the situation of circular tablets, can comprise 30 ° to 180 ° arcs or more preferably 60 to 120 ° of arcs; Under the situation of rectangle, tablet such as trapezoidal, indentation can comprise the about 10% to 50% of tablet girth, and this is to record in the position of containing separation marking.

Term " activating agent ", " active medicine ", " medicine ", " active pharmaceutical composition " and " pharmacologically active agent " can exchange in this article and be meant and cause pharmacological action when being used in organism (mankind or animal) goes up and comprise prescription and the chemical material or the chemical compound as vitamin and cofactor (cofactors) and so on material of OTC (over-the-counter) medicinal compound, pharmacologically effective dose.Under " daily intake of recommendation ", the material of food or vitamin and so on is not considered as " medicine "

Tablet of the present invention prepares with the layering form by add particulate matter continuously in the tablet die head.Particularly, with the formation order of tablet in die head, tablet is described with top, bottom, face, vertical dimensions (or axle), parallel (laterally) dimension (or axle).Thus, the continuous tablet that adds three kinds of different particulate matters and make constitutes three layers of tablet in die head, can be described below: first particulate matter in the die head forms bottom (it is outer); Second particulate matter forms internal layer; The 3rd and last a kind of particulate matter form top layer (it is outer).The theoretical axle that extends to the top from the tablet bottom is a vertical axis, and the vertical direction of indication tablet, does not consider the orientation after tablet leaves die head.With vertical axis or the vertical line of dimension or plane be level or x wire or plane.

Main purpose of the present invention is to allow to pass usually individual chip Dividable tablet easily, but is also included within the Dividable tablet at the interface between a plurality of fragments; Preferred cut zone is the fragment that lacks any medicine of pharmacology effective dose.

If can with various particulate matters flatly (from left to right (side-to-side) place die head continuously but not practice at present like that vertically, the tablet of making so thus also within the scope of the invention because can produce identical product.

When with the vertical substantially direction in surface that estimate to cause tablet fracture place on when the application of force is with separate tablet near separation marking place or separation marking, tablet is cut apart the active component that produces measurable amount.Tablet can be cut apart according to the present invention is following: directly to separation marking or to other zone (for example outside fragment) application of force of tablet, blade for example so that tablet near separation marking place or separation marking along the direction fracture of separation marking.

Separation marking is intended to so that the optional tablet of the known common mode of indentation indication is cut apart, thus with the vertical substantially direction in surface of estimating to cause tablet fracture place near separation marking place or separation marking the application of force with separate tablet.Tablet can be cut apart according to the present invention is following: directly to separation marking or to other zone (for example outside fragment) application of force of tablet, blade for example so that tablet near separation marking place or separation marking along the direction fracture of separation marking.

Accompanying drawing has been described the vertical cross-section diagram of tablet of the present invention and tablettes.Tablet is drawn with their states in die head, thereby makes tablet top on the paper direction corresponding to the top of die head Chinese medicine tablet.In other words, the tablet top fragment of being seen comprises the particulate matter that enters die head at last.Tablettes draws with the state in die head before complete tablet separates with them.

" front view " is meant the sectional view of tablet---it has and marks the theoretical geometrical plane that tablet is relatively passed on the plane of doing the front arbitrarily.The figure (it also has " front view " accordingly) that is designated as " side view " is the cross section of passing the intercepting of whole tablet from the right side of front view, that is to say, side view is to pass with cross-sectional elevational view to be 90 ° the vertical axis of whole tablet and the cross section that intercepts.The schematic cross-section of the mid point (recording to the tablet or the tablette back side from tablet or tablette front) of horizontal cross-section is passed in each front view representative.Front view is also parallel with the main shaft of tablet, for example, and for rectangle (but not being square) tablet cross section, the longer side of periphery and the plane parallel of describing cross-sectional elevational view.The center of this plane between described tablet front and back.

The fragment that shows the medicine that comprises pharmacologically effective dose with section lines; The fragment that lacks any medicine of any medicine or shortage pharmacologically effective dose is represented (no section lines or point are retouched) with blank.The top of every width of cloth figure is equivalent to tablet top, and all these are all drawn with their position situations in die head before releasing after the final compacting and from die head.For self-consistentency, tablettes orientation in the drawings is identical with the tablet of making them, although tablettes produces after tablet forms.Separation marking in the tablet shown in the figure is depicted as and is present on the tablet surface or the indentation in the surface, these indentations can consequently not be presented on the cross-sectional elevational view in tablet by excessively extension on depth direction, reflect the position (not shown) of described indentation on the tablet surface or in the surface with dotted line in these figure.What it is also understood that is, in specific embodiments, the degree of depth of separation marking or other indentation can be darker than half of the wideest cross section of tablet, therefore, represents the horizontal dotted line of surperficial indentation (it is a separation marking) and do not mean that the degree of depth of any indentation that will limit tablet of the present invention.Similarly, represent the dotted line of surperficial indentation not limit horizontal or vertical expanded range (extent) or the height or the degree of depth as the indentation of separation marking.Perforation or interruption indentation are also within the scope of the invention.Laser that can be by having appropriate power and wavelength or make perforation by thin apparatus (thin instrument).Perforation in this article refers to the hole that extends to opposite side (preferred opposition side) from tablet one side, for example " passage ".For simplicity, serve as any indentation of separation marking or typographic(al) mark on the tablet front in this hypothesis, this front is optional from the vertical orientated surface of tablet." side view " of tablet is the tablet sectional view from front view rotation 90 degree.In any figure, do not limit the size of separation marking as dotted lines.Serviceability when in addition, the mark guidance of print separation labelling and so on being cut apart is not set restriction.Describe to have the Tablettes of the break surface shown in serration figure.It is schematically that this sawtooth is described, and does not represent the actual pattern of tablet or tablette fracture.

Fig. 1 a and 1b have described to have the tablet that composition is gone up essentially identical top fragment 40 and below fragment 44.What interior segments 42 contained trace is present in medicine in fragment 40 and 44 with the treatment effective dose.The bottom that the top of fragment 42 and fragment 42 are represented in interface 46 and 48 respectively with the zone of top fragment 40 and below fragment 44 adjacency.Curved interface is to be produced by the profile of the top tablet punch press of bending.Indentation 52 is presented among Fig. 1 b.Dotted line 50 among Fig. 1 a is reflection (not shown)s of indentation 52 on the tablet surface, and it does not penetrate tablet half length than short horizontal.

Fig. 2 a-d has described the tablet of Fig. 1 a and 1b to be cut apart the tablettes that forms by indentation 52.The interior segments 42 of Fig. 1 a is not re-used as the complete slice section and exists.The top tablette of Fig. 1 a and 1c contains the fragment 80 that is connected with complete top fragment 40, and below tablette contains fragment 82 and complete fragment 44.

The tablet of cutting apart Fig. 1 a and 1b by the indentation that is arranged in fragment 42 is obviously easy than passing through its vertical dimensions Dividable tablet, and the latter is the present practice mode of indentation layering (segmentation) tablet.Do not cut apart at the tablet position of containing active medicine, this provides especially accurately for active medicine contained in the tablet cuts apart.

Fig. 3 has shown two fragment tablets, and each fragment is made by the particulate matter of the medicine that contains pharmacologically effective dose.Top (outside) fragment 124 is bigger than below (outside) fragment 126.Interface 128 is meant the zone of described fragment adjoiner.The predetermined cut-point of typographic(al) mark (not shown) representative on the tablet outer surface, this is shown in the position of the arrow 130 of the position of surface printing labelling as described in reflecting.Two fragments also have different colors, this further can discern tablet which partly contain which kind of fragment.

Fig. 4 a and 4b have described the tablet of Fig. 3 is cut apart two tablettes that make.The tablette of Fig. 4 a comprises fragment 118, the major part of the fragment 124 of its representative graph 3 (the bulk).Tablette shown in Fig. 4 b contains the fragment 112 and the fragment 120 of complete form, below half of the fragment 126 of fragment 120 representative graphs 3.Interface 116 is meant the zone of described fragment adjacency.Curved surface is to be produced by the profile of tablet punch press.

Fig. 5 shown with before shown in those compare the more tablet that stretches.This tablet passes a fragment than other easier to be cut apart.Epimere 600 contains the medicine of therapeutic dose; The interior segments 604 that point is painted contains the different pharmaceutical of therapeutic dose; Hypomere 608 contain therapeutic dose with the different medicine of medicine that is present in therapeutic dose in fragment 600 and 604.Barren interior segments 602 and 606 contains every kind of three kinds of medicines that exist of pharmacology ineffective dose in tablet.Two zones in abutting connection with the fragment joint are represented at interface 610,612,614 and 616.The tablet of Fig. 5 provides different colors for each fragment.Even without surperficial indentation or labelling, Color Scheme also can attracting attention passing fragment 602 application of forces with Dividable tablet, thereby produce the tablettes that is painted as Fig. 6 a and 6b.Fig. 6 a has described to pass that fragment 602 is cut apart the tablet of Fig. 5 and the less tablette that produces with landscape mode.Cut apart generation fragment 620 by described, and the fragment 602 of Fig. 5 is not re-used as the existence of complete slice section.Fig. 6 b has described the described big tablette of cutting apart generation by the tablet of Fig. 5.Produce new top fragment 622.

Fig. 7 a-c has described three tablettes cutting apart generation subsequently by the tablette of Fig. 6 b.Produce new segment 630 and fragment 632, and fragment 606 is not re-used as the existence of complete slice section.

Fig. 8 is the perspective view of tablet of the present invention, and it has shown as the indentation 701 of the separation marking on the front and top activity (containing medicine) fragment 702; Middle part inactive segments (medicine that does not have detectable medicine or pharmacology ineffective dose) and bottom active fragment 706.When tablet is cut in indentation 701 punishment, top fragment and bottom fragment still are kept perfectly.

Fig. 9 is the front view of tablet of the present invention, and it has shown band 901, for example is used to seal the gelatin band of hard gelatin capsule, and it is used for suitable tablet of the present invention so that separation marking to be provided.Can revise as U.S.4, disclosed band envelope (band) capsule technique is to provide the band of making tablet of the present invention in 922,682 (they are incorporated herein by this reference).

Figure 10 has shown and can make on the tablet surface to form a series of perforation 100 of separation marking of the present invention.These perforation can be crept into 1-2 millimeter hole by machinery or laser and be formed, and it extends into the degree of depth of surface to the 1-2 millimeter.

Figure 11 has shown the front view of the tablet that contains two printing dotted lines that serve as separation marking of the present invention.

Can make particulate matter according to the prescription that comprises or lack active medicine.The particulate matter that lacks active medicine is the non-activity particulate matter at this.

After the particulate matter different by more than one made tablet, make medicine of the present invention through novel further processing.Preferred embodiment is as follows, but is not limited thereto:

First particulate matter that comprises amlodipine (cardiovascular drug) enters die head, is the non-activity particulate matter then, is then and the essentially identical particulate matter of first particulate matter., handle tablet and indentation is set after the release in tablet press and from die head in the intermediate segment that constitutes by the non-activity particulate matter.Indentation can carry out manual, semi-automatic or automatically.Perhaps, can make the line that is horizontally through described intermediate segment by use printing ink, by technology well known in the art or by using the edible adhesive tape.As another alternative, tablet can be processed and bear laser can be to make one or more (through-and-through) through hole in intermediate segment.All these technology all are provided with separation marking in a fragment or on a fragment, cut apart so that the active medicine of scheduled volume to be provided in each partitioning portion of tablet thereby can accurately carry out tablet; These " halves (bisection parts) " are known as tablettes in this article.The present invention has solved described problem thus---and be no matter whether tablet have indentation, all can not be divided into impartial part as required reliably.The present invention does not require when the intermediate segment of being made by the non-activity particulate matter is applied power tablet is divided into two five equilibriums, but by in above-mentioned example the high concentration active drug being placed the zone different with cut zone, successfully realized its purpose.

Can use other method to help realizing purpose of the present invention according to the present invention.Another technology comprises making to have the fragment of different colours.In above-mentioned example, top and bottom fragment can be with white, and intermediate segment can be green.Green intermediate segment is regarded as separation marking thus, because it has determined the position in the expectation zone when recommending tablet to cut apart described tablet cut apart.

Another embodiment comprises the following particulate matter that adds different pharmaceutical in top and bottom fragment:

The particulate matter that comprises Hydrochlorothiazide (HCTZ) enters die head, is the non-activity particulate matter then, is the particulate matter that comprises ramipril then.With after the compacting of three fragments (with three layers) medicine and from die head, releasing, draw the tablet at quarter by intermediate segment.Thus, apply power with hands or with instrument as cutter or commercially available tablet separator and so on, can easily tablet be cut apart (for example as shown in Figure 3) and become two tablettes, a HCTZ who comprises therapeutic dose, another comprises the ramipril of therapeutic dose, and these two tablettes contain some intermediate segment.Be enough to make the people tablet to be cut apart with the vision that obtains required result (under the situation of indentation or perforation with the invention provides by suitable fragment, and may be by the edible adhesive tape), the fact of tactile data compares, predetermined cut-point is by indentation, printing, other mark, perforation or paints more inessential that color forms.

Medicine of the present invention is not limited to any specific medication amount.They do not need to comprise the fragment of being made by the non-activity particulate matter.For example, can following manufacturing two fragment tablets:

Making two kinds of successive essentially identical particulate matters that comprise microencapsulation potassium chloride goods enter die head, is the particulate matter that comprises furosemide (diuretic) then.Therefore described tablet is two fragment tablets, just the compound fragment of the simple fragment of furosemide and KCl.At final each layer of compacting and after from die head, releasing tablet, can be at all places, for example flatly (laterally) pass the KCl fragment, stroke quarter tablet.Tablet can intactly use as combination product, maybe can cut apart by indentation.Tablettes can be respectively useful naturally; By furosemide be less than the tablette that the KCl of the amount in the whole tablet constitutes and can have therapeutic value, and the KCl that does not contain furosemide substantially also can have therapeutic value.

Some detailed directions of treatment patient or have needs other people or other animal are as follows.List some in the numerous therapeutic agent that can be used in the tablet of the present invention below.

In addition, the present invention can be used for providing the combination tablet in a kind of activating agent of abundant permission and other activating agent mode separated from one another.In can many made in accordance with the present invention products some are described below.

Preferred fabrication scheme is described

Manufacturing contains three segmental height greater than width tablets, has active top or top fragment and active below or bottom fragment separately, and they are separated by the intermediate segment of basic non-activity.Use three layers of rotary tablet machine of Stokes 27-station.All preparations all are the mixture of powderss that can directly suppress.In Patterson-Kelly " V " blender, carry out the mixing of amlodipine preparation and benazepril preparation.Intermediate segment comprises 194 milligrams of Nu-Tab , and does not require mixing.Use 0.131 inch * 0.3222 inch oval concave surface tablet punch press tablet to be depressed into the hardness of 35 kilograms.The die head of at first the bottom fragment being packed into.Tablet weight is 310 milligrams.The tablet of so making is 8 millimeters high; The non-activity intermediate segment is high and 4 mm wides of 5-6 millimeter.

The weight (milligram) that constitutes each segmental particulate matter is as follows:

Bottom fragment milligram

Calcium phosphate dibasic anhydrous 51.13

Amlodipine Besylate Tablet 7.15

Sodium starch glycollate (Explotab ) 2.48

Magnesium stearate 0.93

FD﹠amp; C Blue#1 aluminum color lake 0.31

Add up to 62.00

Make indication

1. each composition is weighed.

2. sieve each composition.

3. use suitable mixer to develop colorant with main diluent with geometric proportion.

4. in from the color mixer of step #3, add all the other compositions except that lubricant and mix required time.

5. in from the mixture of step #4, add lubricant and mix required time.

6. mixture is added in the suitable press be furnished with outfit (tooling) and be pressed into tablet.

The intermediate segment milligram

Nu-Tab  (sompressible sugar (Compressible sugar) 194.00

30/35?N.F.)

Top fragment milligram

One Lactose hydrate 310 42.03

Benazepril hydrochloride 9.00

Polyvinylpolypyrrolidone 2.16

Magnesium stearate 0.54

FD﹠amp; C Red#40 aluminum color lake 0.27

Add up to 54.00

Make indication

1. each composition is weighed.

2. sieve each composition.

3. use suitable mixer to develop colorant with main diluent with geometric proportion.

4. in from the color mixer of step #3, add all the other compositions except that lubricant and mix required time.

5. in from the mixture of step #4, add lubricant and mix required time.

6. mixture is added in the suitable press be furnished with outfit (tooling) and be pressed into tablet.

The tabletting indication

1. the powder with active layer places hopper #1.

2. the powder with placebo layer places hopper #2.

3. the powder with active layer places hopper #3.

4. layer #1 tablet is depressed into required weight (tablet of layer #1 should form soft briquetting).

5. with layer #1﹠amp; Layer #2 tablet is depressed into the required gross weight (tablet should form soft briquetting) of layer #1 and layer #2 weight.

6. three layers of tablet are depressed into required total tablet weight (layer #1 weight+layer #2 weight+layer #3 weight).Tablet should be required hardness.

Use identical as mentioned above top and bottom fragment, but use following ingredients to replace the Nu-Tab of intermediate segment, make similar tablet of the present invention separately.Use Patterson-Kelly " V " blender with the following ingredients fusion.

The composition milligram of intermediate segment

Calcium phosphate dibasic anhydrous 158.59

Magnesium stearate 2.79

PVP?K-30 2.62

Add up to 164.00

Make indication

1. each composition is weighed.

2. sieve each composition.

3. will all the components except that lubricant pack into suitable mixer and mix required time.

4. in from the mixture of step #3, add lubricant and mix required time.

5. mixture is added in the suitable press be furnished with outfit (tooling) and be pressed into tablet.

Use 0.131 inch * 0.3222 inch oval concave surface tablet punch press tablet to be depressed into the hardness of 35 kilograms.The die head of at first the bottom fragment being packed into.Tablet weight is 280 milligrams.Tablet with described intermediate segment is 6 millimeters high, and the non-activity intermediate segment is that the 3.5-4 millimeter is high.

The tabletting indication

1. the powder with active layer places hopper #1.

2. the powder with placebo layer places hopper #2.

3. the powder with active layer places hopper #3.

4. layer #1 tablet is depressed into required weight (tablet of layer #1 should form soft briquetting).

5. with layer #1﹠amp; Layer #2 tablet is depressed into the required gross weight (tablet should form soft briquetting) of layer #1 and layer #2 weight.

6. three layers of tablet are depressed into required total tablet weight (layer #1 weight+layer #2 weight+layer #3 weight).Tablet should be required hardness.

In a similar way, can be at tablet machine (Korsch TRP900 for example, it is because deep fill fills the design of cam and can produce higher tablet, and this cam can produce darker filler and bigger distance between operated pressing tool and the below operated pressing tool up) go up the tablet of other height greater than width of manufacturing.Make 12 millimeters high tablets in order to go up at oval 0.131 inch * 0.3222 inch concave surface KorschTRP900, formulator must be increased to the weight of non-activity Nu-Tab  intermediate segment about 323 milligrams.Similarly, in order to have 14 millimeters final tablet height, with the about 388 milligrams intermediate segment dispensing tablet of weight.If formulator is liked, they can use second example in intermediate layer, just calcium hydrogen phosphate (DCP) prescription.Make 12 millimeters high tablets in this case on oval 0.131 inch * 0.3222 inch concave surface Korsch TRP900, formulator must be increased to the weight of non-activity DCP intermediate segment about 410 milligrams.Similarly, in order to have 14 millimeters final tablet, with the about 492 milligrams intermediate segment dispensing tablet of weight.

The present invention also comprise dosage form by tablet of the present invention and tablettes and so on to needs prevention or treatment disease, keep fit, patient, mammal or other animal of the medicine of slow down aging or other purpose use the method for one or more medicines.Comprise a kind of medicine (novel tablette for example of the present invention) treatment patient's who only uses from combination product method, can regulate dosage for various reasons downwards like this; Perhaps in a similar manner, can upwards regulate dosage thus with a whole tablet treatment patient who comprises the various active medicine and only a kind of medicine of accepting similar tablet again.Can benefit from combination product of the present invention---wherein a kind of medicine is arranged in outside active fragment, second kind of different medicine is arranged in another outside active fragment, and the non-activity intermediate segment in paragraph 3 and the 4 described embodiments as mentioned---comprise and contain those right products of following medicine: amlodipine and benazepril or and chlortalidone or and atorvastatin; Shellfish receives Puli and Hydrochlorothiazide; Olmesartan and Hydrochlorothiazide; With many other types, comprise most of combination product of making at present.The method that also comprises accurate divided dose medicine (it can be 1/2 or 1/4 of a complete dosage, but also can be different marks) the treatment patient who uses available from whole tablet.Warfarin especially can be made and administration according to dosage with separable tablet fragment (its can but need not to be 1/2,1/4 or the like) according to the present invention.Levothyroxinnatrium and digoxin are other examples that can so benefit with warfarin.

Provide possible clinical condition below, tablet wherein of the present invention can provide important benefit.

1. the product of selling in the U.S. at present is Caduet , and it contains active component Atorvastatin calcium (atorvastatin) and Amlodipine Besylate Tablet (amlodipine), and their major parts are dispersed in not in the incising tablet equably mutually.This product is used for the treatment of hyperlipidemia (atorvastatin) and hypertension (amlodipine).The patient who takes this tablet carries out blood test every day and is diagnosed as shown in the rising of enzyme concentration in the blood to have hepatic insufficiency.The doctor recommends to stop (may temporarily stopping) subsequently and takes atorvastatin, and this medicine may cause hepatic insufficiency as described in manufacturer.Therefore the patient who takes Caduet also must withdraw amlodipine, and this is not that the doctor expects in this example.Tablet of the present invention---wherein atorvastatin separately is arranged in different outside active fragment and spaced apart by the enough intermediate segment of size with amlodipine---obviously is better than existing Caduet preparation, because this tablet can make the patient immediately continue to take in amlodipine when stopping to take in atorvastatin, do not fill out new prescription to obtain only to contain the tablet of amlodipine and do not spend the pharmacy, can obtain again before simultaneously these two kinds of medicines are incorporated in convenience in the single dosage form as active component.Above-mentioned embodiment of the present invention has been represented the improvement to existing Caduet dosage form.

Another clinical condition that the present invention is better than Caduet is, takes 5 milligrams of amlodipines every day once, and 20 milligrams of patients once of atorvastatin are increased to 10 milligrams of every days once through doctor's suggestion with amlodipine dosage.The patient who has a competent tablet of the present invention (wherein active medicine separately is arranged in three fragment tablets) adds another full wafer tablet of the present invention is cut apart the tablette that contains 5 milligrams of amlodipines that gets by taking whole piece tablet of the present invention every day, can increase amlodipine dosage immediately.

Another clinical condition that the present invention is better than Caduet is to comprise following situation, and its Chinese physician wishes that the patient takes in 20 milligrams of atorvastatins and every day every morning and takes in 2.5 milligrams of amlodipines twice.The present invention can separate amlodipine and atorvastatin and accurately be divided into two halves subsequently.Therefore the present invention can give the benefit that the patient uses a tablet, and will realize that in the U.S. this point needs one 20 milligrams Lipitor  (atorvastatin) tablets and 2.5 milligrams of tablets of two Norvasc  (amlodipine) at present.

2. the U.S. that is combined in of Amlodipine Besylate Tablet and benazepril hydrochloride (shellfish receive Puli) is that trade mark is sold with Lotrel .This product is the whole as usual capsule of taking.Embodiment of the present invention provide and have comprised and contain amlodipine as the outside fragment of unique active medicine with contain benazepril another segmental complete tablet in outside as unique active medicine.If desired, arbitrary skin can be made more than one fragment as shown in Figure 1a.With above the example 1 about Caduet is the same, intermediate segment be non-activity and can cut apart producing two tablettes by it, the outside active fragment that each tablettes contains complete amount adds the middle inactive segments of almost half amount.If needs of patients doubles a kind of dosage of active medicine, but another kind need not double, and tablet of the present invention just can satisfy these needs.Perhaps, if the patient is because blood pressure or to a kind of medicine but not another kind of situation about having side effects and so on and need only take a kind of active medicine (may be interim), tablet of the present invention can be realized this point under the situation of not leaving new dosage form prescription.

3. another purposes of the present invention comprises the combination of amlodipine and chlortalidone or other diuretic, and they make up usually with treatment hypertension.Benefit of the present invention and the preceding paragraph are described similar.

4. another purposes of the present invention comprises the combination of olmesartan medoxomil (Olmesartan, angiotensin receptor blocker) and Hydrochlorothiazide (HCTZ).This product is sold with the title of Benicar/HCT  in the U.S. at present, and dosage is respectively 20/12.5,40/12.5 and 40/25 milligram.The very general starting dose of patient be every day 20/12.5 once.This product is sold with various concentration as the even tablet that comprises two kinds of active medicines at present.When preparing, can use identical tablet to improve wherein a kind of dosage by half sheet of taking whole 20/12.5 tablet and contain half sheet of 20 milligrams of Olmesartans or contain 25 milligrams of HCTZ with the patient of 20/12.5 dosage begin treatment according to the present invention.This makes the doctor can study this new dosage before leaving new recipe to the patient.Other advantage of the present invention and mentioned above similar.

5. can comprise angiotensin-convertion enzyme inhibitor (ACEs) and diuretic (for example HCTZ) according to the another kind of available combination product of the present invention's preparation.These two kinds of medicines all have side effect usually, so the present invention can make the doctor deal with this side effect and change dosage demand resisting hypertension and other clinical benefit to consider medicine.

6. just active drug is split with regard in the skin that separates with non-activity intermediate segment (layer), can benefit from another product of the present invention is to comprise two kinds of active medicines, the combination product of fluoxetine and olanzapine.

Tablet of the present invention to the object lesson in above-mentioned treatment field or the field without limits, it can be used in any suitable drug regimen.There is not restriction in two drug regimens yet.For example, an outside active fragment of tablet of the present invention can contain levodopa and carbidopa, another outside active fragment can contain entacapone, and the tablet product that contains all these three kinds of medicines in even mode is sold as Stalevo  in the U.S. at present.In addition, tablet of the present invention can comprise five synusia sections, wherein, for example, at amlodipine, the inactive segments that be adjacent, the intermediate segment that contain chlortalidone or HCTZ, second inactive segments of the outside in the fragment---this fragment and intermediate segment and contain another of benazepril outside fragment all in abutting connection with (referring to Fig. 8).Be enough to the size cut apart easily under any situation of three active fragments not destroying if two inactive segments all have, owing to adopt the segmental flexible administration of different activities, can provide significant clinical benefit so.

Following the compiling a name list of feasible multiple drug regimen is illustrative rather than restrictive.The combination of mentioning can comprise two or more in the listed classification.For simplicity, the medicine of listing with this paper below is not mentioned any salt of medicine; For example list " atorvastatin ", although its sale form is an Atorvastatin calcium.

Without limitation, available combination comprises the multiple medicine from following six kinds of drug categories.In addition, tablet of the present invention can be made a kind of medicine that only contains in the following list.For being used in combination, two kinds of usings method are fit to the present invention.The first will singly be planted medicine and be placed a kind of particulate matter and different single medicines (or drug regimen) of planting is placed different particulate matters, may insert the non-activity particulate matter between them; Another kind is that multiple medicine is placed one or more fragments.

1. anti-angina pectoris medicine, for example:

A. calcium antagonist (compiling a name list as follows);

B. beta-Blocking agent (compiling a name list as follows);

C. organic nitrate goods (for example, single nitric acid or Dilatrate-SR).

2. anti-angina pectoris medicine adds antiplatelet drug, for example aspirin, clopidogrel or ticlopidine.

3. two kinds of blood sugar lowering (compiling a name list as follows).

4. potassium chloride and any thiazide or loop diuretic (compiling a name list as follows).

5. lipid lowerers adds: blood sugar lowering, antiplatelet drug, anti-angina pectoris medicine and/or antihypertensive (seeing above and list hereinafter).

Blood sugar lowering comprises: thiazolidinediones: pioglitazone, rosiglitazone; Sulfonylurea: glyburide, glipizide, glimepiride, chlorpropamide;

Biguanides: metformin;

Meglitinides: Nateglinide, repaglinide;

Alpha-glucosidase inhibitors: acarbose, rice lattice class alcohol.

6. antihypertensive:

Beta-Blocking agent: acebutolol, atenolol, bisoprolol, celiprolol, metoprolol, mebivolol, carvedilol (blend alpha-beta-blocker), nadolol, oxprenolol, penbutolol, pindolol, Propranolol, timolol, betaxolol, carteolol;

Calcium antagonist (calcium channel blocker): nifedipine, amlodipine, verapamil, diltiazem, nisoldipine, felodipine, Isradipine, lacidipine, lercanidipine, nicardipine, Manidipine;

Thiazide diuretic (containing or do not contain Potassium-sparing diuretic, for example triamterene, amiloride or spironolactone): Hydrochlorothiazide, chlorothiazide, navidrex, many thiazines, bendroflumethiazide, hydroflumethiazide, chlortalidone, indapamide, methylclothiazide, metolazone;

Angiotensin-convertion enzyme inhibitor: captopril, enalapril, lisinopril, ramipril, trandolapril, quinapril, perindopril, moexipril, benazepril, fosinopril;

Angiotensin receptor blocker: losartan, valsartan, Candesartan, telmisartan, Eprosartan, Irb;

Efficient (medullary loop) diuretic (containing or do not contain Potassium-sparing diuretic, for example triamterene, amiloride or spironolactone): furosemide, torasemide, etacrynic acid, bumetanide;

Aldosterone antagonist diuretic: spironolactone, eplerenone;

α-Zu Zhiji: doxazosin, terazosin, prazosin, indoramine, labetalol (blend alpha-beta-blocker);

Center α-Zu Zhiji: clonidine, methyldopa;

Imidazoline: moxonidine;

Direct effect type vasodilation: hydralazine, minoxidil;

Adrenergic neuron blocking agent: guanethidine.

Lipid lowerers comprises:

Statins: lovastatin, simvastatin, pravastatin, Rosuvastatin, atorvastatin, fluvastatin;

The special class (Fibrates) of shellfish: clofibrate, bezafibrate, fenofibrate, gemfibrozil, ciprofibrate;

Other: ezetimide, nicotinic acid, acipimox.

Drug regimen disclosed herein is to be used to illustrate but not to limit the scope of the invention.

About the tablet of the present invention's's (its relate to be divided into contain similar active fragment with tablet) tablettes and the important application of tablettes, if can carrying out medicine that dosage regulates, majority can cut apart with accurate way, then can be preferred.Especially the example of benefiting from progressive medicine of the present invention after this manner comprises narrow therapeutic index medicine, for example warfarin, digoxin, Levothyroxinnatrium; Vasoactive drug, for example amlodipine; Blood sugar lowering, for example rosiglitazone and glipizide; And antianxiety drugs, for example alprazolam.These just benefit from the sub-fraction in the high amount of drug of various embodiments of the present invention and program.

Dosage form of the present invention comprises its tablet and tablettes, and many usings method are arranged.The professional in medical treatment and pharmacy field will appreciate that various embodiments of the present invention are better than many advantages of existing product.Some examples of benefit of the present invention when relating to the tablet that only contains a similar active fragment are described below.

1. warfarin is the anticoagulant of selling with trade mark Coumadin  in the U.S., and it is a scored tablet.Studies show that the patient can not be divided into 5 milligrams of tablets of warfarin 2.5 milligrams of equal fragments.The present invention has discussed different tablet types, and it can be divided into the warfarin of any human common dose accurate two five equilibriums, and can be divided into accurate trisection, the quartering, or the like.Thus, the patient can use the half sheet warfarin of making according to the present invention under the similar confidence with the complete tablet of use the time.Because warfarin dosage is often cut apart, in many clinical conditions, the present invention can make the patient be benefited.

2. happiness (Amlodipine Besylate Tablet or this paper are called amlodipine) is lived in not 2.5,5 and 10 milligrams of tablets sales of indentation of U.S.'s conduct in the Lip river.These tablets have irregularly shaped and are difficult to be cut apart.The dosage range of FDA approval is oral 2.5 to 10 milligrams of every day.The present invention can improve the occupation mode (functionality) of amlodipine.For example, according to the present invention, to taking 5 milligrams patient every day, if the doctor wishes to increase to 7.5 milligrams of every days, then the patient can use simply and of the present inventionly comprise two 2.5 milligrams of segmental tablets that separate accurately dosage is increased to 7.5 milligrams, for example take complete 5 milligrams of tablets and 2.5 milligrams of tablette, the latter makes by 5 milligrams of tablets are divided into two tablettes that respectively contain 2.5 milligrams of amlodipines.Convenience and cost savings are apparent.Similarly, for taking the patient who lives and like in 10 milligrams of dosage Lip rivers, if be proposed dosage being reduced to 5 milligrams, lives and likes the new recipe of tablet in its 5 milligrams of Lip rivers of necessary at present purchase.The present invention can be divided into two tablettes with 10 milligrams of tablets, and it accurately contains 5 milligrams of amlodipines separately.Therefore the present invention can provide greater flexibility for treating the patient, and saves cost.Further benefit of the present invention is that various embodiments can fully accurately be divided into tablet the tablette of 1/4 dosage that comprises the active component dosage that exists in the whole tablet.For amlodipine, this can followingly realize: four active fragments are provided, and all four all contain 2.5 milligrams of amlodipines, and all with the segmental same edge in the non-activity outside in abutting connection with (referring to embodiment #1; And a) referring to the Fig. 6 that makes four but not two active fragments into.Therefore, 10 milligrams of amlodipines of the present invention can be used for providing 7.5 milligrams of dosage, or can be used for providing four 2.5 milligrams of dosage.

Further benefit of the present invention with can not be relevant with children's or old man's dosage that suitable dose concentration is made.Under the situation of amlodipine, suffer from hypertensive child or suffer from angina pectoris and the aged patient of hypertensive weakness (it may have hepatic insufficiency) in, 1.25 milligrams of daily doses may be effective.Even FDA (Food and Drug Adminstration) (FDA) does not also ratify 1.25 milligrams of dosage, but can produce 1.25 milligrams of daily doses accurately the cutting apart of 2.5 milligrams of dosage of approval.In addition, 2.5 of approval milligrams of dosage accurately cut apart can be accurately with 3.75 milligrams daily dose administration.

Another purposes of the present invention is to provide the method for saving cost for insurance company and patient first.The present invention can realize this point be because, many medicines, for example live happiness and warfarin of Lip river received price difference between (Coumadin) various dose very little (if having poor).Because tablet cuts apart inaccuracy for most scored tablets, all practices that must cut apart of disapprove of most doctors and pharmacists mechanism.Owing to provide accurate dose distribution, the present invention that tablet is cut apart when cutting apart tablet of the present invention (or some tablettes, shown in Fig. 1 b) to have feasibility as described herein.From this innovation, can predict considerable benefit.In addition, the ability that active medicine is separated from one another also provides the cost savings advantage in combination product.

Recognize that related invention can be in spirit disclosed herein.And, the omission among the application be not intended to the inventor be limited in present claims or open in (Alsono omission in current application is intended to limit the inventors to thecurrent claims or disclosures).Although enumerated of the present invention some preferably with selectable embodiment with open the present invention, it may occur to persons skilled in the art that change to disclosed embodiment.

Claims (19)

1. comprise two segmental tablets, one of them is the top fragment, another be the bottom fragment, described tablet at least the one side provide one or more separation markings for it, this separation marking be selected from following one or more:

(a) indentation on one side, wherein said indentation are not vertical orientated;

(b) labelling of the position of the predetermined cut zone of the definite described tablet at least simultaneously;

(c) be positioned on the fragment or be positioned at two fragments band at the interface; Or

(d) sandwich layer of described tablet, wherein the first below fragment has identical color with the second top fragment and comprises the same medicine of pharmacologically effective dose or all lack any medicine of pharmacologically effective dose, with the 3rd inner fragment of inserting, it has and the different color of described first fragment, and it contains and the identical medicine of described first fragment when described first fragment contains the medicine of pharmacologically effective dose, or when described first fragment lacked any medicine of pharmacologically effective dose, it did not contain the medicine of any pharmacologically effective dose.

2. tablet as claimed in claim 1, wherein this separation marking be arranged in a fragment fully or be positioned at two at the interface segmental.

3. tablet as claimed in claim 1, wherein this separation marking is in comprising three segmental tablets, wherein this separation marking be positioned at be not on the segmental individual chip in top or bottom or among.

4. tablet as claimed in claim 3 wherein contains at least one additional separation marking in as the segmental one or more fragments in top or bottom.

5. tablet as claimed in claim 1, wherein this separation marking comprises indentation.

6. tablet as claimed in claim 5, the described separation marking that wherein comprises indentation is to be orientated substantially parallel on described tablet.

7. tablet as claimed in claim 5, the described separation marking that wherein comprises indentation is limited in the fragment substantially.

8. tablet as claimed in claim 5, the described separation marking that wherein comprises indentation are limited in the interface between the fragment substantially.

9. tablet as claimed in claim 1, wherein this separation marking comprises mark.

10. tablet as claimed in claim 1, wherein this separation marking comprises the printing mark.

11. tablet as claimed in claim 1, wherein this separation marking comprises that the dosage that comprises track, printing mark, printing arrow, numeral or other type is indicated or the printing mark of coded digital.

12. tablet as claimed in claim 1, wherein this separation marking comprises a plurality of indentations.

13. tablet as claimed in claim 1, wherein this separation marking is in containing the segmental tablet of three arranged verticals, wherein this separation marking is only in the interior segments that is clipped between top and the bottom fragment, described separation marking flatly is positioned on the tablet, and wherein this trunnion axis is corresponding with the trunnion axis of the tablet die head used of the described tablet of compacting.

14. tablet as claimed in claim 3, wherein this separation marking is in the segmental tablet of the adjacency that contains three arranged verticals, wherein this separation marking is arranged in and is not the segmental individual chip in top or bottom, and described top fragment and described bottom fragment contain identical or different medicine.

15. a method of cutting apart tablet as claimed in claim 1, it is included in described separation marking place or cuts apart described tablet by described separation marking.

16. one kind ruptures by the fragment that has a different colours with adjacent segment that makes described tablet and to cut apart the method for tablet as claimed in claim 1.

17. one kind by rupturing described tablet to cut apart the method for tablet as claimed in claim 1 between the two or more separation markings that comprise track, printing arrow or surface.

Cut apart described tablet to form two or more tablettes and human patients or other living person or animal are used at least one described tablettes 18. a method of using the divided dose of contained drug in the tablet as claimed in claim 1, described method are included in described separation marking place or separation marking is indicated as described.

19. a tablet as claimed in claim 1, wherein said medicine are that pharmacology is effective in cardiovascular disorder, psychosis, diabetes, thyroid function imbalance, pain or thrombotic treatment of diseases.

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