CN1964703A

CN1964703A - Immediate release pharmaceutical tablets with height greater than width

Info

Publication number: CN1964703A
Application number: CN200580016366.7A
Authority: CN
Inventors: L·所罗门; A·S·卡普兰
Original assignee: Accu Break Technologies Inc
Current assignee: Accu Break Technologies Inc
Priority date: 2004-05-21
Filing date: 2005-05-23
Publication date: 2007-05-16
Anticipated expiration: 2025-05-23
Also published as: CN1960713A; CN1993111A; ZA200610683B; ZA200610682B; ZA200610681B; CN1964703B; CN1960712A; CN1997331A; CN1960712B

Abstract

An immediate release compressed pharmaceutical tablet that has two or more segments and a top and a bottom and has a height that exceeds the width of the tablet. The height is measured vertically from the top to the bottom of the tablet while it is in the tablet die in which it is fully compressed, after compression has been completed. The width is measured as the greatest horizontal dimension of the tablet at a location halfway between the top and the bottom of the tablet, except that when the horizontal cross-section of the tablet is substantially rectangular, the width is defined by locating the two shorter sides of the perimeter of the horizontal cross-section, and measuring the length of a line that is at right angle to the shorter sides.

Description

The immediate release pharmaceutical tablets of height greater than width

Technical field

The invention provides tall and big in wide rapid release heterogeneous body slugging, the described novel shape of immediate release pharmaceutical tablets is accurately cut apart the advantage that produces the unexposed mistake of prior art aspect (break) at tablet, tablet cuts apart the active component that more is easy to generate measurable amount thus.

Background technology

The tablet of divided form that contains the indenture that is known as indentation is long-term known and widely-used.The problem that exists when cutting apart incising tablet 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.

Many medicines need dosage to regulate, warfarin (warfarin) for example, and its scored tablet is often separated.Cut apart these dosage that carry out by the patient by tablet and regulate that to be confirmed to be coarse.As described below, the expert appeals that always pharmaceuticals industry improves the quality that tablet is cut apart for many years, but does not also 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 can produce more not satisfied result when thinking patient's actual use.Stimpel appeals that pharmaceuticals industry improves the accuracy of Dividable tablet: " any obviously is wrong about tablet can not caused the imagination of inaccuracy dosage in two the time.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 address the above problem by improving severability (as metoprolol and logroton are done), or better, so that being provided, all dosage that may use in clinical solve the problems referred to above by selling more kinds of no incising tablets.”

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: " function of improving 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: " many in the recent period about the report of the line of weakness of function difference ", " many scored tablets are difficult to cut apart " " two halves that are divided into again through many scored tablets 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. " Breakingof scored 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 " aged patient " through 50-79 year implement and have been cut apart.Peek, B.T., Al-Achi, A., and Coombs, S.J. " Accuracy of TabletSplitting by Elderly Patients. " The Journal of the American MedicalAssociation 288 No.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, 5 milligrams of tablets that on average are divided into 1.9 and 3.1 milligrams of warfarin.This effective anticoagulant has so narrow therapeutic domain so that has prepared 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., " OralAnticoagulant Drugs:Do Not Cut Tablets in Quarters. " Thromb Haemost1201 (1999).In addition, they confirm, cutting apart the mass loss that cracked (crumbling) or break (chipping) that cause cause by the 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 25 milligrams of not incising tablets for 12.5 milligrams of more expenses of tablet payment making separately.

People such as Rosenberg (2002) have studied the Dividable tablet that the pharmacists leaves.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 unacceptable high weight differential incidence rate ".They advise " should set up the standard of the isotropism of guaranteeing Dividable tablet ".

People such as Teng (2002), in laboratory is provided with trained personnel's Dividable tablet, reach a conclusion and be " major part in 11 medicines of our test; when they are divided into the ability of the two halves tablet that dosage equates when evaluation, by testing through (liberallyinterpreted) of just explanation USP (American Pharmacopeia) isotropism ....For saving cost or improving the scheme of dosage regimen Dividable tablet ... do not recommend the patient that will use medicine with bigger toxicity and precipitous dose-response efficacy profile " Teng; J.; Song; C.K.; Williams; R.L., and Polli, J.E. " Lack of Mdication Dose Uniformity in Commonly SplitTablets. " Journal of American Pharmaceutical Association 42 No.2 (2002): 195-199.

Rodenhuis proposes, in the research of a Holland (Netherlands), 31% in all tablets before swallowing through dividing again.In the U.S., many " health care " insurance institution encourages the patient to cut apart indentation even tablet that do not have symmetric shape.In the U.S., although many medicines all do not have indentation or can make tablet to provide with capsule form.

The present invention relates to improvement to the problems referred to above.

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 part is 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.Through generally inferring only about half of can not the treatment to realize the target blood pressure with maximum tolerated dose 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 or pharmacists can't be separated from one another with activating agent.Sica, D., Drugs, 2002; 62 (3): " Rationale for Fixed-Dose Combinations in the Treatment ofHypertension " claims: " there is tradition quite of a specified duration in combined therapy; trace back to the 1950's " 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 have greatly corrected this shortcoming: " shortcoming of using the fixed dosage combination is that every kind of component lacks the dosed administration motility, although the doctor seldom farthest utilizes the inherent dosed administration motility of independent assortment purposes.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 increased the complexity of dosage regimen and may have negative effect to compliance (compliance).In addition, the fixed dosage combined therapy can not provide enough medication amount to treat disease, as common and hypertension and pharyngalgia of depositing or congestive heart failure.”

The present invention can adjust the method for improving above-mentioned condition that provides flexibly by permission dosage in combination dosage forms.

The invention describes and be fit to the pill shapes that the fragment of arranged vertical is separated from one another.In the big field of rapid release pharmaceuticals, the relative size of this tablet is novel.Commercial, unique to be made into tall and big be Concerta  in wide product, and it is three fragment tablets, and wherein two fragments are used for active medicine, the controlled release of methylphenidate.Concerta adopts OROS  system, and it utilizes tall and big in the ingredient of wide geometric construction as its controlled release characteristic.Manufacturer is about the indication explanation of Concerta usage, and this tablet must not be cut apart.

Except that Concerta, tablet (comprise and contain in vertical direction the tablet of the layer of stack arrangement each other) is made into to be wider than height.

Tablet machine manufacturer, the Korsch AG of Germany have developed the tablet machine of the layer that can make maximum 5 stack arrangements in vertical direction.It has been used to make and has not wherein contained the tall and big in five wide synusia agent of active medicine, also is used to make Concerta.

Summary of the invention

The present invention relates to contain two or more fragments, contain the rapid release slugging of top and bottom and height greater than width, after finishing described compacting, when tablet is arranged in the tablet mould that it is fully suppressed, from described tablet top to the described height of bottom vertical survey; Described width is half position between the described top of described tablet and described bottom, the maximum horizontal size of the tablet that measures, but when the horizontal cross-section of described tablet was rectangle substantially, following definite width---two that find out described horizontal cross-section periphery than minor face and measurement and the described line segment length rectangular than minor face.

The preferred embodiment of rapid release slugging is to comprise the segmental tablet that two or more stacks are each other arranged.

The present invention relates to immediate release pharmaceutical tablets, preferably comprise the medicine of pharmacologically effective dose, the height of its Chinese medicine tablet (vertical dimension) surpasses its width (horizontal size), and promptly tablet is tall and big in wide.The term of tablet of the present invention " vertically " and " level " (" level " is also referred to as " laterally ") axle be by the tablet die head (slugging therein) in tablet machine or other pelleter (this paper is called " tablet machine ") definite and have a same orientation of order that enters die head with tablet die head and particulate matter.

Tablet of the present invention most preferably in high speed tablet press with the commercial size manufacturing.In the die head of described tablet machine, make tablet.In this machine, a kind of suffering of particulate matter enters the tablet die head a kind ofly, and described like this particulate matter has just formed described being vertically aligned with each other.The layer and the fragment that are made of the particulate matter of arranged vertical also are regarded as arranged vertical.Measurement enters distance between the high-order bit (described first particulate matter constitutes bottom, and described final granule thing constitutes top layer) of minimum position and the final granule thing that enters die head of first particulate matter of die head as the height of tablet.

Width is level (laterally) size.When measuring width, if the cross section of tablet is rectangle substantially, not carrying out diagonal by the level orientation of tablet measures: if the circumference of the level orientation of tablet is rectangle (not being square), the tablet width is to be generally used for describing one bigger in orthogonal two kinds of peripheral measurement results so, but not by Pythagorean theorem and the diagonal that uses described peripheral measurement result to calculate.Similarly, the height with tablet of orthogonal substantially vertical cross-section structure is the result that periphery is measured, and the result that off-diagonal records.When horizontal or vertical cross-sectional configuration is not basic rectangle when (comprising triangle, rhombus and hexagon), represent described height or width by the full-size in described cross section.

The accurate divided dose that is present in the medicine in the whole tablet if desired, many preferred tablets of the present invention use and do not contain the fragment of pharmacology effective dose of medicine thing as cut zone.In this article for simplicity, term " contains medicine " when a kind of particulate matter that is used to describe tablet, one deck or a fragment, is meant to have pharmacology effective dose of medicine thing in described particulate matter, layer or the fragment.Term " contains medicine " when being used to describe multiple particulate matter, layer or fragment (for example two kinds of particulate matters or two kinds of fragments), is meant in described particulate matter, layer or the like to have pharmacology effective dose of medicine thing.Term " contains one or more medicines " when being used to describe a kind of particulate matter, one deck or a fragment, is meant that particulate matter, layer or fragment can contain single kind medicine, or the multiple medicine of specific ratios.When using " containing one or more medicines " when describing a plurality of fragments, layer or particulate matter, this term is meant that multiple particulate matter, layer or fragment can contain single multiple medicine of planting medicine or specific ratios.

If described layer or fragment do not contain any described medicine or contain the described medicine of pharmacology ineffective dose, then layer or fragment (but not being particulate matter) are called as " suffering for want of medical supplies ".

About above-mentioned two sections, " comprise " " containing ", " comprising " that with the part of speech of " shortage " and so on also be the buzzword that has with identical implication described herein.

In preferred embodiments, but not restrictively, the present invention includes the compacting immediate release pharmaceutical tablets, wherein in fragment, comprise one or more medicines, wherein:

(a) described tablet comprises the two or more fragments that contain one or more identical medicines with identical or different concentration (for the excipient that exists in the described fragment), and the medicine that exists in described fragment, this tablet does not contain another medicine; Or

(b) described tablet comprises two or more fragments, and each fragment contains one or more different medicines;

(c) described tablet comprises first fragment that contains one or more medicines; Second fragment; With the 3rd fragment that contains one or more medicines different with the medicine that exists in described first fragment, described second fragment be inserted in described first and described the 3rd fragment between (promptly below one of described fragment and above another), and described second fragment does not contain described one or more medicines.

(d) described tablet comprises first fragment that contains one or more medicines; Second fragment; With the 3rd fragment that contains the medicine identical with medicine in described first fragment, described second fragment be inserted in described first and described the 3rd fragment between, and described second fragment does not contain described one or more medicines.

In a more preferred embodiment, tablet of the present invention has distinct fragment at least two compositions, and wherein first fragment contains one or more active medicines of pharmacologically effective dose, and second fragment is as follows:

(a) contain the medicine identical but concentration is lower, or in described fragment, contain identical medicine ratio with described medicine in described first fragment; Or

(b) do not contain described one or more medicines that exist in described first fragment, and this tablet also has the 3rd fragment---this fragment contain with described first fragment in the identical medicine that exists; Or

(c) do not contain described one or more medicines in described first fragment, and described tablet also has the 3rd fragment---this fragment contain with described first fragment in one or more all different medicines of any medicine, the wherein said first and the 3rd fragment the chemistry and physically compatible;

(d) contain with described first fragment in the different medicine of medicine, and also comprise the 3rd fragment---this fragment contain with described first fragment in the identical medicine that exists.

Further preferred embodiment can be chosen wantonly on the tablet one side or comprise the indication that tablet is cut apart that is used for such as indentation, mark, printing mark, perforation, contrast color fragment in the face, and wherein the preferred basic horizontal of indentation is so that tablet is cut apart the interface of only passing between a fragment or the fragment carries out.The one side of tablet is the tablet outside that has with the vertical component of the theoretical vertical axis almost parallel of tablet; One side contacts with the inwall or the surface of tablet die head (suppressing described tablet therein).

Compare with traditional tablet of making at present, of the present inventionly tall and bigly be designed to the shape that the easier theoretical vertical axis (promptly in parallel direction) that passes tablet is cut apart in wide tablet with " being wider than height " structure.Many advantageous applications of tablet of the present invention are to disconnect the tablet that does not contain pharmacology effective dose of medicine thing to insert fragment, and the fragment above or below the described insertion fragment is disconnected.

Main purpose of the present invention provides the immediate release pharmaceutical tablets cut apart easily so that the divided dose of one or more medicines contained in the described tablet to be provided.

Purpose of the present invention provides in addition and contains three segmental immediate release pharmaceutical tablets, one of them is to insert fragment, this fragment is fit to disconnect in such a way: if described tablet disconnects by described insertion fragment, then this disconnection is kept perfectly the fragment of one or more medicines that contain pharmacologically effective dose of this fragment above and below.

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

Description of drawings

Fig. 1 a is when impressed tablet face is watched, and is tall and big in the cross section of wide tablet;

Fig. 1 b is when watching the tablet face of indentation end, the cross section of the tablet of figure la;

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

Fig. 3 be contain two segmental tall and big in the cross section of wide tablet, one of them fragment is about 4/3 of a tablet length;

Fig. 4 a-b is when at the approximate midpoint place of tablet tablet having been disconnected, the view of Fig. 3;

Fig. 5 be contain 5 segmental tall and big in the cross section of wide tablet;

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

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

Fig. 8 is the cross section that is wider than height and contains two segmental tablets.

Detailed Description Of The Invention

Tablet of the present invention is preferably those that suppress in tablet press machine. Use for commerce, can With three (3)-or five (5)-punch die number (station) press that use that Korsch AG makes. Remington ' s Pharmaceutical Sciences 20^thEd., Mack Publishing Co., Easton, Pa. (2000), the 45th chapter (it is incorporated herein by this reference) described for the manufacture of The various technology of compressed tablets. Tablet of the present invention is mainly used in oral, but they also can be used for Other purposes. Tablet of the present invention does not use cement, glue, adhesive or analog to form, And preferably uncoated.

Tablet of the present invention comprises at least two and forms different fragments.

Fragment represents the whole continuous of tablet of the present invention or tabloid (tablette) (seeing below) Basic uniformly part. If it is basic identical to enter two or more continuous particulate things of die head, When compacting, they consist of a fragment so. This fragment is a kind of somatotype of fragment, its Can specifically be called combined fragment (compound segment). But, if two kinds substantially not With particle (for example contain the identical active medicine of different activities medicine, different ratios, no Particle with the different salt of the similar excipient of excipient or different ratios or identical active medicine Thing) when suppressing each other, they consist of two fragments. Comprise phase for excipient If with the identical active medicine of concentration but the particle that comprises different excipient in each other compacting The time, then consist of two fragments.

By a certain amount of single particle matter being added the tablet die head to fill at least a portion die head Make thus layer. No matter it is not tamped, tamps or particle of abundant compacting, all looks For there being one deck.

In many most preferably tablets of the present invention, layer (with the particle that consists of this layer) does not need Place above or below the essentially identical layer (or particle) (for example adjoin or in abutting connection with). In this case, one deck consists of a kind of fragment somatotype---and be simple fragment. Term " fragment " Use can refer to simple fragment or combined fragment.

Because tablet of the present invention is fit to cut apart as required, for described the main of generation of cutting apart breaks Term of sheet (fragment) exploitation is verified to be useful. The inventor uses in this regard Term " tabloid (tablette) ". The example that tabloid forms is as follows. Single indentation list with standard Layer homogeneous tablet dividing. Produce two main parts (it is (little to be known as separately tabloid described cutting apart Tablet)), usually also add some chips and sliver (preferred seldom amount). At branch of the present invention In the section layering tablet, suitably utilize the present invention can be advantageously in fragment (for example interior segments) On indentation is set, as the instrument with file and so on carries out. By described indentation successfully Cut apart described tablet and can produce two tabloid s, represent two main parts of tablet, but do not wrap Draw together sliver or chip and so on than minute fragment. Accompanying drawing helps to illustrate the relation of tablet and tabloid.

Term " activating agent ", " medicine ", " active medicine ", " active pharmaceutical composition " and " medicine The reason activating agent " can exchange and include, but not limited to prescription and OTC medicinal compound And the vitamin of pharmacology effective dose, confactor (cofactors) and analog. " pushing away The daily intake of recommending " under, the material of food or vitamin and so on is not considered as " medicine " at this

Term " can not detection limit " refers to use traditional analysis technology, for example high performance liquid chromatography Method (HPLC), Magnetic resonance imaging (NMRI) and similar techniques can not be confirmed active ingredient The existence of thing. Term " pharmacology ineffective dose " refers to not have to survey the medication amount of pharmacodynamics effect. By In the operating condition of high-speed automated sheeting equipment, in the tablet forming process, may produce difference The mixing of particle, this can cause the material of medicine of existing in a kind of particle and so on to occur In layer or fragment that it should not exist.

The term fragment of non-activity " relatively " but refer to not contain any medicine of detection limit or contain Reduce the effectively sheet of one or more medicines of any pharmacology contained in the other fragment of concentration Section.

Term used herein is be used to general understanding rather than restrictive is provided.

As the example of the manufacture method of preferred tablet of the present invention, at first, will contain pharmacology has The particle of medicine of effect dosage pack into die head and compacting. Then, the particle of medicine will do not contained (" non-activity particle ") pack into die head and the compacting. Randomly, another is not contained active medicine The non-activity particle also pack into die head and the compacting. The non-activity particle produces the part of tablet, This part can be identified and disconnect so that contain the tablet part of obvious drug concentration and can not break Split. At last, second particle that will contain the medicine of the pharmacologically effective dose die head of packing into, the optional rammer Real, suppress at last to form compressed tablets. Although one or all fragments can have greatly independently In the width of height, but tablet integral body has the height greater than width. After forming tablet, appoint Selection of land can arrange indentation in described tablet one side, preferred horizontally set indentation. Perhaps, After forming tablet, the mark of track or other form can be set on the tablet surface, example Such as dotted line, symbol or perforation, all these are all for the medicine that contains the discrete dosages medicine from realization The expectation cut zone of the described tablet of angle recognition of the accurate separation of sheet part. Can use it It helps to identify the method in the zone that may need to carry out tablet dividing, for example in different fragments The middle contrastive colours that use.

The suitable dimension of tablet of the present invention is: height: 6 to 24mm; Preferred 10 to 18mm, More preferably 10 to 14mm; Width (the widest size of trunnion axis): 2 to 16mm; Preferred 3 To 10mm, more preferably 4 to 8mm. Without limitation, if the height-width ratio is about 1.5: 1 To about 3: 1, then the tablet size was best.

Can make many other structures, some of them are following describing further. By having The tablet of stating shape can produce various in the treatment of the human patients that needs are arranged and other animal Advantage.

Tablet of the present invention most preferably forms in high speed tablet press. In typical fabrication schedule, Use different loading terminals (stations) particle that two or more are the different mould of packing into separately Head. Wet granulation is preferably transferred to the another kind from a kind of particle with limiting material usually. Powder The direct pressing at end also is preferred manufacturing technology.

Particle produces layer entering fully of loading terminal. Tablet of the present invention has hierarchy. This may be with to add two kinds of continuous essentially identical non-activity particles two-layer identical to form Adjoining course is relevant. After compacting, by the tablet part of described two kinds of identical particle things formation Be known as fragment. The clip types that so forms is known as combined fragment. In fragment of needs In contain in the situation of a large amount of active components, also have reason to make two kinds that contain described active component Essentially identical particle enters at two continuous loading terminals, thus shape after final compacting Become tablet, contain the combined fragment of active medicine. Situation is more usually, wherein with first The grain thing die head (not essentially identical particle (layer) top) of packing into forms layer, will be substantially The particle of not identical (namely different) pack into subsequently described die head, thus described first particle Form not the layer with essentially identical layer adjacency. Described first particle forms quilt in compressed tablets Be considered as the layer of simple fragment.

Benefit of the present invention comprises preferably utilizes the non-activity particle, more not preferred, utilizes and other One fragment is compared the fragment of the drug concentration with reduction. Best, provide identification for tablet Good cut zone and after tablet dividing with a tabloid and other means of another phase region, If tabloid contains one or more medicines of dissimilar or different amounts, this is important benefit The place.

Since the novelty of tablet, necessary top, bottom, the face of describing tablet, etc. According to Find, based on the formation of described tablet with in die head, form on the basis, position of described tablet, Best with these term description tablets.

When using with tablet, " parallel " used herein (" laterally ") and " vertical " And so on term when being based on tablet and in die head, making and after making but breaking away from or releasing die head Spatial orientation before. The following manufacturing tablet of present manufacture method: a kind of particle is contained in Alternative top enters die head, and the tablet of the present invention that this mode is made comprises one or many Individual top (outside) fragment, one or more bottom (outside) fragment and optional one or A plurality of centres (inside) fragment. It or not the sheet of top or bottom (being referred to as " outside ") fragment Section is regarded as interior segments, although interior segments also has outside the time certainly. Interior segments Quantity do not limit.

The bottom fragment of tablet contains first particle that enters die head. The top fragment of tablet contains The particle that enters at last die head is arranged. " side " of tablet refers to and makes that described tablet uses The outside of the described tablet of the inner vertical surface of tablet die head or orientation contact. Usually, with this Bright top is relative with the bottom, the lateral vertical orientation of tablet of the present invention. At tablet top cup In the prominent or situation of cut sth. askew (this is often very serious), the tablet side also is deemed to be included in and uses The described cupping that die stamping forms, cut sth. askew etc. before with inner vertical surface or the side of tablet die head The tablet outside of position contact.

If with various particles flatly (side by side) continuously but not as in the at present practice Vertically place die head, the tablet of making so thus also within the scope of the invention because Can produce identical product. For example, when the tablet of Fig. 1 was placed on flat table when upper, its often with its The mode that forms in die head puts vertically at right angles that (just, its major axis is with respect to table The face level is put), if three fragments are different colours like this, fragment looks and is not so Arranged vertical (one is stacked in another top), but horizontal (being arranged side by side). For The uniformity of term, these fragments still are regarded as superposeing ground each other at this owing to its manufacture Arranged vertical.

Major advantage of the present invention is the tablet dividing that its optimization is optional. When the power that applies to cut apart During tablet, compare with " being wider than height " tablet with the fragment that contains the same medicine amount, past Toward the easier active component that in tabloid, produces measurable amount. Can pass through according to the present invention Directly come Dividable tablet to the zone that will disconnect or to the lateral film section application of force (for example blade), Interior segments can be disconnected in any situation.

The example of specific embodiments of the present invention is fully described with reference to accompanying drawing. Shadow region representative by The fragment that active particle thing (particle that namely contains medicine) is made; The white space representative is by nothing The fragment that active particle thing (particle that namely is mixed with without active medicine) is made.

Accompanying drawing has been described the vertical cross-section diagram of tablet of the present invention and tabloid. Tablet with they State in the die head is drawn, thereby makes tablet top on the paper direction corresponding to the die head Chinese medicine tablet The top. In other words, the tablet top fragment of seeing comprises the particle that enters at last die head. Tabloid is drawn from the state in die head before with them and complete tablets separated.

" front view " is meant the sectional view of tablet---it has and marks the theoretical geometrical plane that tablet is relatively passed in the side 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 whole tablet intercepting from the right side of front view, that is to say that side view is to pass with cross sectional elevation to be the cross section that 90 ° the plane of passing through whole tablet vertical axis intercepts.The schematic cross-section of the mid point (from the tablet front to tablet or the tabloid back side record) of horizontal cross-section is passed in the representative of each front view.Front view is also parallel with the main shaft of tablet, for example, and for tablet, the longer sides in the periphery and the plane parallel of describing cross sectional elevation with rectangle (but not being square) cross section.Half position between described tablet front and back, this plane.The side view of Fig. 1 a-b and Fig. 2 a-b is the plane from the vertical orientation of the mid point by cross section longer sides (that is, wide), thereby these side views are positioned at the mid point of front view, and with this middle point vertical.

The fragment of representing to comprise one or more medicines of pharmacologically effective dose with section lines; The pharmacology invalid fragments is represented (no section lines or point are retouched) with blank.The top of every width of cloth figure is corresponding to tablet top, and all these are all drawn with their location status in die head before releasing after the final compacting and from die head.For self-consistentency, tabloid orientation in the drawings is identical with the tablet of making them, although tabloid is made after tablet is released from die head.Dotted line in the tablet shown in the figure can represent typographic(al) mark or other mark be present on the tablet surface or indentation, if they represent indentation, described indentation can not be carved into tablet too far so that be presented on the cross sectional elevation.The horizontal dotted line of the representative indentation shown in these figure does not also mean that the degree of depth of any indentation that will limit tablet of the present invention.The horizontal dotted line of the surperficial indentation of representative is schematically on the front view, must not represent the complete vertical depth of indentation, typographic(al) mark or analog.

Tabloid is depicted as the break surface that has shown in the serration pattern.It is schematically that this sawtooth is described, and does not represent the actual pattern of tablet or tabloid fracture, even described tablet separates by indentation, it also produces broken edge usually.

Compare with layering known in the art (segmentation) tablet, use and of the present inventionly tall and bigly can more easily arrest and cut apart described tablet in wide design, wherein, if feasible, only pass the requirement of a fragment Dividable tablet by its longest axle " incision (filleting) " tablet.

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 tablet upper punch of bending (upper tablet punch).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 tabloid 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 tabloid of Fig. 1 a and 1c contains the fragment 80 with complete top fragment 40 adjacency, and the below tabloid 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.The fact of not cutting apart at the tablet position of containing active medicine for tablet in contained active medicine provide especially accurately and cut 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 shown in the position of arrow 130 on the tablet outer surface, this arrow 130 has reflected the position of described surface printing labelling.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 tabloid s that make.The tabloid of Fig. 4 a is made of fragment 118, the major part of fragment 124 (the bulk) in its representative graph 3.Tabloid shown in Fig. 4 b contains the fragment 112 and the fragment 120 of complete form, in its representative graph 3 below half of fragment 126.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 more elongated tablet.Described tablet passes a fragment than other easier and disconnects.Top fragment 600 contains the medicine of therapeutic dose; The interior segments 604 that point is painted contains the different pharmaceutical of therapeutic dose; Below fragment 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 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 make tablet pass fragment 602 disconnections to apply power, thereby produces the tabloid s 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 tabloid 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 tabloid of cutting apart generation by the tablet of Fig. 5.Produce new top fragment 622.

Fig. 7 a-c has described three the tabloid s cutting apart generation subsequently by the tabloid 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 shows two traditional fragment tablets.In this tablet, below (bottom) fragment 324 contain with top (top) fragment 322 in contained different medicine.Indentation 328 is carved in the fragment 324.There is interface 326 in

fragment

322 and 324 zones that engage.The tablet of Fig. 8 is not a tablet of the present invention.It has shown the sketch map of the prior art tablet of layer tablets.Will readily recognize that and attempt only to cut apart as the tablet of Fig. 8 or similarly, but below fragment 324, also have the inherent difficulty of segmental tablet with Fig. 8 is similar by a fragment level.

Benefit of the present invention is not limited to contain the tablet of any given number active component.All fragments that contain active component can comprise identical medicine, or these fragments can comprise different medicines.

In order to fully realize benefit of the present invention, can be in the fragment of tablet (or between the fragment at the interface) indentation is set.Can use file in interior segments, to form this indentation, therefore can when outside fragment is kept perfectly, cut apart by interior segments by described indentation Dividable tablet in the mode of basic horizontal.

In addition, can follow the method for similar manufacturing tablet, edible ink for example is set on tablet, describe the desired zone of tablet thus, for example fragment in the middle of it.This usage is as known in the art.Other method that applies mark is regarded as within the scope of the invention.

Embodiment

Preferred fabrication scheme is described

Manufacturing contains three segmental " tall and big in wide " 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 the 8mm height; The non-activity intermediate segment is that 5-6mm is high and 4mm is wide.

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 required machining tool (tooling) and be pressed into tablet.

The intermediate segment milligram

Nu-Tab  (sompressible sugar 30/35 N.F.) 194.00

Top fragment milligram

One Lactose hydrate 310 42.03

Benazepril HCl 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.

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

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. layer #1﹠ 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 have 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 respectively.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 required machining tool (tooling) and be pressed into tablet.

Use oval 0.131 inch * 0.3222 inch 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 the 6mm height, and the non-activity intermediate segment is the 3.5-4mm height.

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.

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.

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 design allows darker filler and bigger distance between operated pressing tool and the below operated pressing tool up) other is tall and big in wide tablet to go up manufacturing.In order to make high 0.131 inch * 0.3222 inch concave surface tablet of ellipse of 12mm on Korsch TRP900, formulator must be increased to the weight of non-activity Nu-Tab  intermediate segment about 323 milligrams.Similarly, in order to have the final tablet height of 14mm, 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 high 0.131 inch * 0.3222 inch concave surface tablet of ellipse of 12mm in this case on KorschTRP900, formulator must be increased to the weight of non-activity DCP intermediate segment about 410 milligrams.Similarly, in order to have the final tablet of 14mm, 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 tabloid s and so on to needs prevention or treatment disease, keep fit, patient, mammal or one or more medicines of other animals administer of the medicine of slow down aging or other purpose.Comprise a kind of medicine (novel tabloid 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---and comprise and contain those right combination products of following medicine: a kind of in amlodipine and benazepril, chlortalidone or the 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 (it can be 1/2 or 1/4 of a complete dosage, but also can be different marks) the treatment patient who uses from the medicine of whole tablet.Warfarin especially can be made and administration according to dosage with the separable fragment of tablet (its can but need not 1/2,1/4 or the like) according to the present invention.Levothyroxinnatrium and digoxin are other examples that can so benefit except that warfarin.

Providing tablet of the present invention below can provide the possible clinical setting of 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 every day can carry out blood test then and be diagnosed as hepatic insufficiency (shown in the rising of enzyme concentration in the blood).The doctor recommends to stop (may temporarily stopping) subsequently and takes atorvastatin, and this medicine may cause hepatic insufficiency as described in manufacturer.Yet, take the patient of Caduet so the amlodipine of also having to withdraw, this is not that the doctor expects in this example.Tablet of the present invention---wherein atorvastatin and amlodipine lay respectively in the different outside active fragments and be spaced apart by the enough intermediate segment of size---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 before these two kinds of medicines to be incorporated in the convenience in the single dosage form simultaneously again 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 once a day, and atorvastatin 20 milligrams patient once a day increases to 10 milligrams once a day 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 tabloid that contains 5 milligrams of amlodipines that gets by taking a 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 comprises 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 make the patient have the benefit of using 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 embodiment 1 about Caduet is the same, intermediate segment be non-activity and can disconnect producing two tabloid s, the outside active fragment that each tabloid s 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 of undouble, 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 temporary transient), 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.This 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 is once a day 20/12.5.This product is sold with various effectiveness (strength) as the homogenizing tablet that comprises these two kinds of active medicines at present.When preparing, can use identical tablet this dosage to be increased to every kind of other 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 have an opportunity to 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 deal with and is that treatment resisting hypertension and other clinical benefit change the demand of drug dose.

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 with homogeneous manner is sold as Stalevo  in the U.S. at present.In addition, tablet of the present invention can comprise five synusia sections, for example, wherein 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 dosage administration of different activities, can provide significant clinical benefit so.

The list of following 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 can comprise 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.One of method is that independent a kind of medicine is placed a kind of particulate matter and the only only medicine (or drug regimen) of different another kinds is placed different particulate matters, may insert the non-activity particulate matter between them; Another kind method 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;

MAG replaces anti-(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, methyl chlorothiazide (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: ezetimibe (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 present invention's's (it relates to tablet is divided into the tabloid s that contains similar active fragment) tablet and the important application of tabloid s, can cut apart with accurate way if can carry out most medicines that dosage regulates, then this application is preferred.Especially the example of benefiting from progressive medicine of the present invention thus 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 can 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 tabloid s, 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 that relate to the benefit of the present invention of 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, for the patient who takes 5 milligrams every day, if the doctor wishes that it increases 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 tabloids, the latter makes by 5 milligrams of tablets being divided into two tabloid s 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 of every days, 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 tabloid s 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 1/4 the tabloid 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 contains four but not two active fragments instead.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 is with can not to render a service children's or the old man's dosage made with suitable dosage relevant.Under the situation of amlodipine, suffer from hypertensive child or suffer from pharyngalgia and the aged patient of hypertensive weakness (it may have hepatic insufficiency) in, 1.25 milligrams of daily doses may be effective.Although FDA (Food and Drug Adminstration) (FDA) does not also ratify 1.25 milligrams of dosage, 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 cuts apart permission 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, most doctors and pharmacists mechanism all disapprove carry out mandatory (mandatory) and cut apart.Owing to provide accurate dose distribution, the present invention that tablet is cut apart when cutting apart tablet of the present invention (or some tabloid s, 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 content that the present invention ignores is not that the inventor is limited in claim of the present invention and the description scope.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

1. contain the rapid release slugging of two or more fragments and top and bottom and height greater than width, described height is after finishing described compacting, when tablet is arranged in the tablet die head that it is fully suppressed, obtain from described tablet top to bottom vertical survey; The position of half between the described top of described tablet and described bottom, the maximum horizontal dimension of measuring tablet is as described width, but when the horizontal cross-section of described tablet is rectangle substantially, following definite width---find out in the periphery of described horizontal cross-section two than minor face and measure and the described line segment length rectangular than minor face.

2. rapid release slugging as claimed in claim 1, this tablet comprise the fragment that two or more stacks are each other arranged.

3. rapid release slugging as claimed in claim 2, the fragment of this tablet contain one or more identical medicines.

4. rapid release slugging as claimed in claim 3, wherein with respect to the inactive excipients in each fragment, to weight, described tablet contains two or more fragments with one or more different drug level in weight.

5. rapid release slugging as claimed in claim 3, it comprises three fragments, first fragment is that fragment is inserted in the inside between second fragment and the 3rd fragment, described inner one or more medicines that insert the basic non-activity of fragment or contain the pharmacology ineffective dose, described second fragment is the top fragment, described the 3rd fragment is the below fragment, and the described second and the 3rd fragment is basic identical.

6. rapid release slugging as claimed in claim 3, it contains the core texture that is made of tablet as claimed in claim 5.

7. rapid release slugging as claimed in claim 2, it contains the fragment of two arranged verticals, and they contain one or more medicines of pharmacologically effective dose separately, and wherein described one or more medicines in each arranged vertical fragment are different.

8. rapid release slugging as claimed in claim 7, it is made of two fragments.

9. rapid release slugging as claimed in claim 7, it is made of first fragment, the second and the 3rd fragment, wherein first fragment is to insert fragment in the inside between the fragment below fragment above in the of second and the 3rd, and described second contains one or more different medicines with the 3rd fragment.

10. rapid release slugging as claimed in claim 9, wherein the tablet of claim 10 is core textures of bigger tablet.

11. rapid release slugging as claimed in claim 2 wherein is not that all arranged vertical fragments are all basic identical.

12. rapid release slugging as claimed in claim 2 be not in the segmental fragment in top or bottom indentation to be set wherein.

13. rapid release slugging as claimed in claim 2 be not in the segmental fragment in top or bottom described tablet to be applied typographic(al) mark or other mark wherein, it has determined the position of the expectation cut zone of described tablet.

14. rapid release slugging as claimed in claim 2 wherein essentially horizontally is provided with indentation on the tablet one side.

15. rapid release slugging as claimed in claim 2 wherein determines that a position is as estimating cut zone on the one side at described tablet in that typographic(al) mark or other mark essentially horizontally are set on the one side of described tablet.

16. what rapid release slugging as claimed in claim 5, the wherein said second and the 3rd fragment occupied described tablet height separately is no more than 20%.

17. what rapid release slugging as claimed in claim 16, the wherein said second and the 3rd fragment occupied described tablet height separately is no more than 10%.

18. cut apart the method for rapid release slugging as claimed in claim 1, wherein described tablet cut apart by its shortest dimension.

19. cut apart the method for rapid release slugging as claimed in claim 1, wherein said tablet is only cut apart by a fragment.

20. by cutting apart rapid release slugging as claimed in claim 2 to produce the method for accurate medication amount.

21. the method for one or more medicines of following administration doses: cut apart rapid release slugging as claimed in claim 2, produce tabloid thus, and to patient or other people or the described tabloid of other animals administer of needs.

22. to the method for accurate divided dose that the medicine in the patient's administration rapid release slugging as claimed in claim 2 that needs is arranged, this method comprises cuts apart described tablet to produce one or more tabloids, subsequently to the described tabloid of described patient's administration.

23. tablet as claimed in claim 1, wherein said one or more medicines are that pharmacology is effective in cardiovascular disorder, psychosis, diabetes, thyroid function imbalance, pain or thrombotic treatment.