CN1964703B - Immediate release pharmaceutical tablets with height greater than width - Google Patents
Immediate release pharmaceutical tablets with height greater than width Download PDFInfo
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- CN1964703B CN1964703B CN2005800163667A CN200580016366A CN1964703B CN 1964703 B CN1964703 B CN 1964703B CN 2005800163667 A CN2005800163667 A CN 2005800163667A CN 200580016366 A CN200580016366 A CN 200580016366A CN 1964703 B CN1964703 B CN 1964703B
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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
Technical field
The invention provides tall and bigly in wide rapid release heterogeneous body slugging, the said 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, and 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 adjustments, warfarin (warfarin) for example, and its scored tablet is often separated.It is coarse cutting apart through tablet that these dosage adjustments of carrying out have been confirmed to be by the patient.Be described below, the expert appeals that always pharmaceuticals industry improves the quality that tablet is cut apart for many years, but before the present invention, does not also reach optimum efficiency.
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 through improving severability (as metoprolol and logroton are done); Or better, so that being provided, all dosage that possibly use in clinical solve the problems referred to above through 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).N. people such as Rodenhuis, " The rationale of scored tablets as dosage form. " European J.of Pharmaceutical Sciences 21 (2004): 305-308 (hereinafter is 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 maybe be relevant with scenario: " 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 processing 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, through 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, and in the research of a Holland (Netherlands), the warp before swallowing of 31% in all tablets divides 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 process 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 partly is described below:
Association area of the present invention is the composition of medicine treatment field that is used for systemic arterial property 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 to treat 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 of Hypertension " 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, the just independent prescription of needs.This has increased the complexity of dosage regimen and possibly have negative effect to compliance (compliance).In addition, the fixed dosage combined therapy can not provide enough medication amount to treat disease, like 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 through 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; It is unique that to be made into tall and big be Concerta
in wide product; It is three fragment tablets; 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 accomplishing said compacting; When tablet is arranged in the tablet mould that it is fully suppressed, from said tablet top to the bottom the said height of vertical survey; Said width is position half the between the said top of said tablet and said bottom; The maximum horizontal size of the tablet that measures; But when the horizontal cross-section of said tablet is rectangle basically, confirm width as follows---two that find out said horizontal cross-section periphery than minor face and measurement and the said line segment length rectangular than minor face.
The preferred embodiment of rapid release slugging is to have three fragments; First fragment is that fragment is inserted in the inside between second fragment and the 3rd fragment, the said inner fragment non-activity that inserts, and said second fragment is the top fragment; Said the 3rd fragment is the below fragment; The stack on perpendicular to the direction of tablet width of said three fragments is arranged, and the said second and the 3rd fragment contains one or more medicines of pharmacologically effective dose, and what the wherein said second and the 3rd fragment occupied said tablet height separately is no more than 20%; What preferably, the said second and the 3rd fragment occupied said tablet height separately is no more than 10%.
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 through the tablet die head (slugging therein) in tablet machine or other pelleter (this paper is called " tablet machine ") definite and have and the order the same orientation of tablet die head with particulate matter entering die head.
Tablet of the present invention most preferably in high speed tablet press with the commercial size manufacturing.In the die head of said tablet machine, make tablet.In this machine, a kind of suffering of particulate matter gets into the tablet die head a kind ofly, and said like this particulate matter has just formed described being vertically aligned with each other.The layer and the fragment that are made up of the particulate matter of arranged vertical also are regarded as arranged vertical.Measure to get into distance between the high-order bit (said first particulate matter constitutes bottom, and said final granule thing constitutes top layer) of minimum position and the final granule thing that gets into 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 basically; Not carrying out diagonal through 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 through Pythagorean theorem and the diagonal that uses said peripheral measurement result to calculate.Similarly, the height with tablet of orthogonal basically 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 said height or width through the full-size in said 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 the fragment that does not contain 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 said 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 said 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 said layer or fragment do not contain any said medicine or contain the said 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) said 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 said fragment), and the medicine that in said fragment, exists, this tablet does not contain another medicine; Or
(b) said tablet comprises two or more fragments, and each fragment contains one or more different medicines;
(c) said tablet comprises first fragment that contains one or more medicines; Second fragment; With the 3rd fragment that contains the medicine different drug that exists in one or more and said first fragment; Said second fragment be inserted in said first and said the 3rd fragment between (promptly below one of said fragment and above another), and said second fragment does not contain said one or more medicines.
(d) said tablet comprises first fragment that contains one or more medicines; Second fragment; With contain with said first fragment in the 3rd fragment of the identical medicine of medicine, said second fragment be inserted in said first and said the 3rd fragment between, and said second fragment does not contain said 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 following:
(a) contain with said first fragment in the identical medicine of said medicine but concentration is lower, or in said fragment, contain identical medicine ratio; Or
(b) do not contain said one or more medicines that exist in said first fragment, and this tablet also has the 3rd fragment---this fragment contain with said first fragment in the identical medicine that exists; Or
(c) do not contain said one or more medicines in said first fragment; And said tablet also has the 3rd fragment---this fragment contain with said first fragment in one or more all different medicines of any medicine, the wherein said first and the 3rd fragment the chemistry with physically compatible;
(d) contain with said first fragment in the medicine different drug, and also comprise the 3rd fragment---this fragment contain with said 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 be have with the tablet of the vertical component of the theoretical vertical axis almost parallel of tablet outside; One side contacts with the inwall or the surface of tablet die head (suppressing said tablet therein).
Compare with traditional tablet of processing at present, of the present inventionly tall and bigly be designed to pass more easily the shape that the theoretical vertical axis (promptly in parallel direction) of tablet is cut apart in wide tablet with " being wider than height " structure.Many advantageous applications of tablet of the present invention are to break off the tablet that does not contain pharmacology effective dose of medicine thing to insert fragment, and the fragment above or below the said insertion fragment is broken off.
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 said tablet to be provided.
The object of the invention provides in addition and contains three segmental immediate release pharmaceutical tablets; One of them is to insert fragment; This fragment is fit to break off in such a way: if said tablet breaks off through said 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, of the present invention these become obvious with other purpose.
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 Fig. 1 a;
Fig. 2 a-d is respectively when having broken off tablet through 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 midpoint place of tablet tablet having been broken off, 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 broken off, 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 breaking off, 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 in tablet machine, suppress.For commercial application, three (3)-or five (5)-punch die number (station) press that can use that Korsch AG makes.Remington ' s Pharmaceutical Sciences 20
ThEd., Mack Publishing Co., Easton, Pa. (2000), the 45th chapter (it is quoted through this and incorporates this paper into) has been described the various technology that are used to make compressed tablet.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, binding agent or analog to form, and preferably uncoated.
Tablet of the present invention comprises at least two and forms different fragments.
Fragment is represented the whole successive basic part uniformly of tablet of the present invention or tabloid (tablette) (seeing below).If it is basic identical to get into two or more continuous particulate matters of die head, when compacting, they constitute a fragment so.This fragment is segmental a kind of typing, and it can specifically be called compound fragment (compound segment).But; If when on each other, suppressing, they constitute two fragments to two kinds of different basically particulate matters (particulate matter of different salt that for example contains similar excipient or the identical active medicine of the identical active medicine of different activities medicine, different ratios, different excipient or different ratios).If when the particulate matter that comprises the identical active medicine of same concentrations for excipient but comprise different excipient is suppressed, then constitute two fragments on each other.
Come to make thus layer through a certain amount of single particle matter being added the tablet die head to fill at least a portion die head.No matter it is not tamped, tamps or particulate matter of abundant compacting, all is regarded as existing one deck.
In many most preferably tablets of the present invention, layer (with the particulate matter that constitutes this layer) need not place above or below the essentially identical layer (or particulate matter) (for example adjoin or in abutting connection with).In this case, one deck constitutes a kind of fragment typing---and be simple fragment.The use of term " fragment " can refer to simple fragment or compound fragment.
Because tablet of the present invention is fit to cut apart as required, be useful for said term of main part (fragment) exploitation of cutting apart generation is verified.The inventor use a technical term in this regard " tabloid (tablette) ".The example that tabloid forms is following.Single indentation monolayer homogenizing tablet of standard is cut apart.Produce two main parts (being known as tabloid (tabloid) separately) said cutting apart, and also adds some chips and sliver (preferred very small amount) usually.In staged and layered tablet of the present invention, suitably utilize the present invention advantageously on fragment (for example interior segments), indentation to be set, as the instrument with file and so on carries out.Successfully cut apart said tablet through said indentation and can produce two tabloid s, represent two main parts of tablet, but do not comprise 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 " pharmacologically active agent " can exchange and comprise; But be not limited to vitamin, cofactor (cofactors) and the analog of prescription and OTC medicinal compound and pharmacology effective dose.Under " daily intake of recommendation ", the material of food or vitamin and so on is not regarded as " medicine " at this
Term " can not detection limit " is meant and uses the traditional analysis technology that for example HPLC (HPLC), NMR-imaging (NMRI) and similar techniques can not be confirmed the existence of reactive compound.Term " pharmacology ineffective dose " is meant the medication amount that does not have to survey pharmacodynamics effect.Because the operating condition of high-speed automated sheeting equipment, the mixing that in the tablet forming process, possibly produce the variable grain thing, the material of medicine that this can cause in a kind of particulate matter, existing and so on appears in its layer or fragment that should not exist.
The term fragment of non-activity " relatively " but be meant any medicine that does not contain detection limit or contain the fragment of effective one or more medicines of any pharmacology contained in the other fragment that reduces concentration.
Term used herein is to be used to provide general understanding rather than restrictive.
As the example of the manufacturing approach of preferred tablet of the present invention, at first, the particulate matter that will contain pharmacology effective dose of medicine thing pack into die head and compacting.Then, with the particulate matter of drug (" non-activity particulate matter ") not pack into die head and compacting.Randomly, with another non-activity particulate matter that does not contain active medicine also pack into die head and the compacting.The non-activity particulate matter produces the part of tablet, and this part can be identified and break off so that contain the tablet part of obvious drug level and can not rupture.At last, second particulate matter that will contain the medicine of the pharmacologically effective dose die head of packing into, optional compacting is suppressed to form compressed tablet at last.Although one or all fragments can have the width greater than height independently, tablet integral body has the height greater than width.After forming tablet, randomly, can on said tablet one side, indentation be set, preferred horizontally set indentation.Perhaps; After forming tablet; The mark of track or other form can be set on the tablet surface, for example dotted line, symbol or perforation, all these all are used for discerning from the angle of the clean cut separation of the tablet part that realizes containing the discrete dosages medicine expectation cut zone of said tablet.Can use other to help to discern the method that to carry out the zone that tablet cuts apart, for example in different fragments, use contrast color.
The suitable dimension of tablet of the present invention is: height: 6 to 24mm; Preferred 10 to 18mm, and more preferably 10 to 14mm; Width (the wideest size of trunnion axis): 2 to 16mm; Preferred 3 to 10mm, and more preferably 4 to 8mm.Without limitation, if height-width is than being about 1.5: 1 to about 3: 1, then the tablet size is best.
Can make many other structures, some of them are further described as follows.Tablet through having said shape can produce various advantages in the treatment of the human patients that needs are arranged and other animal.
Tablet of the present invention most preferably forms in high speed tablet press.In typical fabrication schedule, use different loading terminals (stations) particulate matter that two or more are the different die head of packing into separately.Wet granulation is preferably transferred to the another kind from a kind of particulate matter with limiting material usually.The direct compacting of powder also is preferred manufacturing technology.
Particulate matter produces layer in the entering fully of loading terminal.Tablet of the present invention has hierarchy.This maybe be relevant to form two-layer identical adjoining course with two kinds of successive essentially identical non-activity particulate matters of interpolation.After compacting, the tablet that forms through said two kinds of identical particle things partly is known as fragment.The clip types that so forms is known as compound fragment.In fragment of needs, contain under the situation of a large amount of active component; Also have reason to make two kinds of essentially identical particulate matters that contain said active component to get at two successive loading terminals; After final compacting, form tablet thus, contain the compound fragment of active medicine.Situation more generally is; Wherein with first particulate matter die head (not essentially identical particulate matter (layer) top) of packing into; The particulate matter that cambium layer will be inequality basically (promptly different) the said die head of packing into subsequently, said thus first particulate matter form not the layer with essentially identical layer adjacency.Said first particulate matter forms in compressed tablet and is regarded as simple segmental layer.
Benefit of the present invention comprises preferably utilizes the non-activity particulate matter, more not preferred, utilizes the fragment of comparing the drug level with reduction with another fragment.Best, for tablet identification optimal segmentation zone is provided and after tablet is cut apart with a tabloid and other means of another phase region, if tabloid contains one or more dissimilar or not commensurability medicines, this is important benefit.
Since the novelty of tablet, necessary top, bottom, the face of describing tablet, or the like.According to finding, form on the basis, position of said tablet based on the formation of said tablet with in die head, be best with these term description tablets.
When using with tablet, the term of " parallel " used herein (" laterally ") and " vertical " and so on is based on tablet when in die head, making with process the back but break away from or release die head before spatial orientation.Present manufacturing approach is made tablet as follows: a kind of particulate matter is contained in alternative top gets into die head; The tablet of the present invention that this mode is made comprises one or more tops (outside) fragment, one or more bottom (outside) fragment and optional one or more centres (inside) fragment.Not that the segmental fragment in top or bottom (being referred to as " outside ") is regarded as interior segments, although interior segments also has outside the time certainly.The quantity of interior segments is not limit.
The bottom fragment of tablet contains first particulate matter that gets into die head.The top fragment of tablet contains the particulate matter of last entering die head." side " of tablet is meant and the inner vertical surface of making the tablet die head that said tablet uses or the outside of the said tablet that the orientation contacts.Usually, relative with top of the present invention and bottom, the lateral vertical orientation of tablet of the present invention.At tablet top cupping or under the situation of cut sth. askew (this is often very serious), the tablet outside that the tablet side contact with the inner vertical surface or the orientation of tablet die head before also being regarded as and being included in the said cupping using die stamping and form, cut sth. askew or the like.
If with various particulate matters flatly (side by side) continuously but not as in the practice at present, vertically place die head, the tablet of processing so thus also within the scope of the invention because can produce identical product.For example; When the tablet of Fig. 1 is placed on flat table last time; It often at right angles vertically puts (just, its major axis is put with respect to the desktop level) with the mode that it forms in die head, if three fragments are different colours like this; Fragment looks and is not arranged vertical (is stacked in another top) so, but horizontal (being arranged side by side).For the concordance of term, these fragments are because its manufacture still is regarded as stack ground arranged vertical each other at this.
Major advantage of the present invention is it and optimizes optional tablet and cut apart.When applying power with Dividable tablet, compare with having segmental " being wider than height " tablet that contains the same medicine amount, often in tabloid, produce the active component of measurable amount more easily.Can under any situation, can interior segments be broken off according to the present invention through directly coming Dividable tablet to the zone that will break off or to the lateral film section application of force (for example blade).
The example of specific embodiments of the present invention is fully described with reference to accompanying drawing.The fragment that the shadow region representative is processed by active particle thing (particulate matter that promptly contains medicine); The fragment that the white space representative is processed by non-activity particulate matter (particulate matter that promptly is mixed with without active medicine).
Accompanying drawing has been described the vertical cross-section diagram of tablet of the present invention and tabloid.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 of last entering die head.State before tabloid separates with complete tablet with them in die head is drawn.
" 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 to be 90 ° the plane of passing through whole tablet vertical axis and the cross section of intercepting with cross sectional elevation.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 the position between said 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 through 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 processing them, although tabloid is processed 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, said 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 said tablet separates through 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 said tablet in wide design; Wherein, if feasible, only pass the requirement of a fragment Dividable tablet through 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.Interior segments 42 contain trace with the treatment effective dose be present in the medicine in fragment 40 and 44. Interface 46 and 48 represent fragment 42 top and fragment 42 the bottom 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 through indentation 52.The interior segments 42 of Fig. 1 a no longer exists as complete fragment.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 through the indentation that is arranged in fragment 42 is obviously easy than passing through its vertical dimension 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 processed 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 said 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 said surface printing labelling.Two fragments also have various 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 process.The tabloid of Fig. 4 a is made up 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 fragment 120 of complete form, in its representative graph 3 below fragment 126 half the.Interface 116 is meant the zone of said 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.Said tablet breaks off than other the fragment of passing more easily.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 medicine different drug that is present in therapeutic dose in fragment 600 and 604.Barren interior segments 602 and 606 contains three kinds of medicines that in tablet, exist of pharmacology ineffective dose.Two zones in abutting connection with the fragment joint are represented at interface 610,612,614 and 616.The tablet of Fig. 5 provides various 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 like 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 through said, and the fragment 602 of Fig. 5 exists as complete fragment no longer.Fig. 6 b has described the said big tabloid of cutting apart generation through the tablet of Fig. 5.Produce new top fragment 622.
Fig. 7 a-c has described three the tabloid s cutting apart generation subsequently through the tabloid of Fig. 6 b.Produce new segment 630 and fragment 632, and fragment 606 exists as complete fragment no longer.
Fig. 8 shows two traditional fragment tablets.In this tablet, below (bottom) fragment 324 contain with top (top) fragment 322 in contained different drug.Indentation 328 is carved in the fragment 324.There is interface 326 in the zone that engages in fragment 322 and 324.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 like the tablet of Fig. 8 or similarly, but below fragment 324, also have the inherent difficulty of segmental tablet with Fig. 8 is similar through 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 drug.
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 through interior segments through said indentation Dividable tablet with 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 wherein between fragment.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.At first with the bottom fragment die head of packing into.Tablet weight is 310 milligrams.The tablet of so processing is that 8mm is high; 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&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. add mixture in the suitable press be furnished with required machining tool (tooling) and be pressed into tablet.
The intermediate segment milligram
Nu-Tab
(sompressible sugar 30/35N.F.) 194.00
Top fragment milligram
One Lactose hydrate 310 42.03
Benazepril HCl 9.00
Polyvinylpolypyrrolidone 2.16
Magnesium stearate 0.54
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. add mixture in the suitable press be furnished with required machining tool (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. 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 stated 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
PVPK-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. add mixture 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.At first with the bottom fragment die head of packing into.Tablet weight is 280 milligrams.Tablet with said intermediate segment is that 6mm is high, and the non-activity intermediate segment is that 3.5-4mm 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. 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.
According to similar fashion; 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 on Korsch TRP900, to make high 0.131 inch * 0.3222 inch concave surface tablet of ellipse of 12mm, formulator must be increased to about 323 milligrams with the weight of non-activity Nu-Tab
intermediate segment.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.On KorschTRP900, make high 0.131 inch * 0.3222 inch concave surface tablet of ellipse of 12mm in this case, 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 through 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 drug is arranged in another outside active fragment, and like the non-activity intermediate segment in preceding text paragraph 3 and the 4 described embodiments---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 except that warfarin, can so benefit.
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
; 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 each other.This product is used to treat 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 (possibly temporarily stopping) subsequently and takes atorvastatin, and this medicine such as manufacturer are said possibly to cause hepatic insufficiency.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 superior to existing Caduet preparation; Because this tablet can make the patient when stopping to take in atorvastatin, immediately continue to take in amlodipine; Do not fill out new prescription to obtain only to contain the tablet of amlodipine and do not spend the pharmacy, before obtaining again simultaneously these two kinds of medicines are incorporated in the 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 superior to 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 through taking a whole piece tablet of the present invention every day, can increase amlodipine dosage immediately.
Another clinical condition that the present invention is superior to Caduet comprises following situation, and its Chinese physician hopes 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 20 milligrams of Lipitor
(atorvastatin) tablet 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 comprise 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 processed more than one fragment shown in Fig. 1 a.The same with preceding text about the embodiment 1 of Caduet, intermediate segment be non-activity and can break off 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 (possibly 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 with treatment hypertension usually.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, ARB) and Hydrochlorothiazide (HCTZ).This product is sold with the title of Benicar/HCT
in the U.S. at present; Dosage is respectively 20/12.5; 40/12.5; With 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 with half sheet that contains half sheet of 20 milligrams of Olmesartans or contain 25 milligrams of HCTZ this dosage to be increased to every kind of other dosage through taking whole 20/12.5 tablet with the patient of 20/12.5 dosage begin treatment according to the present invention.This makes the doctor leave new recipe to the patient before, have an opportunity to study this new dosage.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 is to not restriction of the object lesson in above-mentioned treatment field or the field, and 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 with 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, significant clinical benefit can be provided 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 processed a kind of medicine that only contains in the following list.Use for combination, two kinds of methods for using 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, possibly between them, insert the non-activity particulate matter; 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 the antihypertensive list of hereinafter (see above with).
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;
ARB: losartan, valsartan, Candesartan, telmisartan, Eprosartan, Irb;
Efficient (medullary loop) diuretic (containing or do not contain Potassium-sparing diuretic, for example triamterene, amiloride or spironolactone): FRS, 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;
Shellfish special type (Fibrates): clofibrate, bezafibrate, fenofibrate, gemfibrozil, ciprofibrate;
Other: ezetimibe (ezetimide), nicotinic acid, acipimox.
The disclosed drug regimen of this paper is to be used to illustrate and unrestricted scope of the present 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 of dosage adjustments, 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 embodiment of the present invention and program.
Dosage form of the present invention comprises its tablet and tabloid s, and many methods for using are arranged.The professional in medical treatment and pharmacy field will appreciate that various embodiment of the present invention is superior to 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.Research shows that the patient can not be divided into 2.5 milligrams of equal fragments with 5 milligrams of tablets of warfarin.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 processing 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 hopes 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 processes through 5 milligrams of tablets being divided into two tabloid s that respectively contain 2.5 milligrams of amlodipines.Convenience and cost savings property are obvious.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 practices thrift cost.Further benefit of the present invention is that various embodiments can be fully accurately be divided into 1/4 the tabloid that comprises the active component dosage that exists in the whole tablet with tablet.For amlodipine, this can realize as follows: 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 possibly have hepatic insufficiency) in, 1.25 milligrams of daily doses possibly 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 be that insurance company and patient provide the method for practicing thrift cost 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 (11)
1. the rapid release slugging of height greater than width is characterized in that said height is after accomplishing said compacting, when tablet is arranged in the tablet die head that it is fully suppressed, what vertical survey obtained to the bottom from said tablet top; Half the position between the said top of said tablet and said bottom; The maximum horizontal size of measuring tablet is as said width; But when the horizontal cross-section of said tablet is rectangle basically; Following definite width---measure and the said line segment length rectangular than minor face than minor face for two that find out in the periphery of said horizontal cross-section, this length is width; Said tablet has three fragments; First fragment is that fragment is inserted in the inside between second fragment and the 3rd fragment; The said inner fragment non-activity that inserts, said second fragment is the top fragment, said the 3rd fragment is the below fragment; The stack on perpendicular to the direction of tablet width of said three fragments is arranged; The said second and the 3rd fragment contains one or more medicines of pharmacologically effective dose, and what the wherein said second and the 3rd fragment occupied said tablet height separately is no more than 20%, is provided for the indication that tablet is cut apart in said first fragment.
2. rapid release slugging as claimed in claim 1, wherein said second contains one or more different medicines with the 3rd fragment.
3. rapid release slugging as claimed in claim 1 wherein saidly is used for the indication that tablet cuts apart and is selected from indentation, mark, printing mark, perforation and contrast color fragment.
4. rapid release slugging as claimed in claim 1, wherein said to be used for the indication that tablet cuts apart be indentation.
5. rapid release slugging as claimed in claim 1, wherein said to be used for the indication that tablet cuts apart be typographic(al) mark.
6. rapid release slugging as claimed in claim 4 wherein essentially horizontally is provided with said indentation on the first fragment side.
7. rapid release slugging as claimed in claim 5 wherein essentially horizontally is provided with said typographic(al) mark on the first segmental side.
8. what rapid release slugging as claimed in claim 1, the wherein said second and the 3rd fragment occupied said tablet height separately is no more than 10%.
9. the method for cutting apart rapid release slugging as claimed in claim 1, wherein said tablet is cut apart through first fragment.
10. through cutting apart rapid release slugging as claimed in claim 1 to produce the method for accurate medication amount.
11. 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.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57304204P | 2004-05-21 | 2004-05-21 | |
| US57313404P | 2004-05-21 | 2004-05-21 | |
| US60/573,134 | 2004-05-21 | ||
| US60/573,042 | 2004-05-21 | ||
| PCT/US2005/018633 WO2005112897A2 (en) | 2004-05-21 | 2005-05-23 | Immediate release pharmaceutical tablets with height greater than width |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1964703A CN1964703A (en) | 2007-05-16 |
| CN1964703B true CN1964703B (en) | 2012-07-04 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580016277 Pending CN1993111A (en) | 2004-05-21 | 2005-05-23 | Pharmaceutical tablets containing relative inactive segments |
| CN2005800163652A Active CN1960712B (en) | 2004-05-21 | 2005-05-23 | Incising tablet including a plurality of segment |
| CN 200580016367 Pending CN1960713A (en) | 2004-05-21 | 2005-05-23 | Tablet including two or more unit segment |
| CN 200580016276 Pending CN1997331A (en) | 2004-05-21 | 2005-05-23 | Pharmaceutical tablets with separation marking on one side thereof |
| CN2005800163667A Expired - Fee Related CN1964703B (en) | 2004-05-21 | 2005-05-23 | Immediate release pharmaceutical tablets with height greater than width |
Family Applications Before (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580016277 Pending CN1993111A (en) | 2004-05-21 | 2005-05-23 | Pharmaceutical tablets containing relative inactive segments |
| CN2005800163652A Active CN1960712B (en) | 2004-05-21 | 2005-05-23 | Incising tablet including a plurality of segment |
| CN 200580016367 Pending CN1960713A (en) | 2004-05-21 | 2005-05-23 | Tablet including two or more unit segment |
| CN 200580016276 Pending CN1997331A (en) | 2004-05-21 | 2005-05-23 | Pharmaceutical tablets with separation marking on one side thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (5) | CN1993111A (en) |
| ZA (3) | ZA200610682B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780079B (en) * | 2010-03-03 | 2011-10-05 | 施慧达药业集团(吉林)有限公司 | Levamlodipine compound drug composition |
| CN102247367B (en) * | 2011-05-24 | 2014-05-21 | 苏州东瑞制药有限公司 | Pharmaceutical composition containing telmisartan and amlodipine and preparation method thereof |
| CA3095341A1 (en) * | 2018-03-29 | 2019-10-03 | Avion Pharmaceuticals, Llc | Levodopa fractionated dose composition and use |
| CN111407734A (en) * | 2019-01-05 | 2020-07-14 | 厦门赛诺邦格生物科技股份有限公司 | Solid preparation of medicine for treating impotence and premature ejaculation |
| EP4115879A1 (en) * | 2019-07-31 | 2023-01-11 | Intas Pharmaceuticals Ltd. | Pharmaceutical composition comprising hmg-coa reductase inhibitors and fenofibrate |
| CN110515288A (en) * | 2019-09-27 | 2019-11-29 | 珠海天威飞马打印耗材有限公司 | Cartridge |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4353887A (en) * | 1979-08-16 | 1982-10-12 | Ciba-Geigy Corporation | Divisible tablet having controlled and delayed release of the active substance |
| DK152744C (en) * | 1982-08-13 | 1988-10-31 | Benzon As Alfred | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PERORAL POLYDEPOT PREPARATION |
| US4999226A (en) * | 1988-06-01 | 1991-03-12 | Merrell Dow Pharmaceuticals Inc. | Pharmaceutical compositions for piperidinoalkanol-ibuprofen combination |
| US5061494A (en) * | 1990-06-14 | 1991-10-29 | The Upjohn Comany | Tri-scored drug tablet |
| CN2421015Y (en) * | 2000-05-01 | 2001-02-28 | 董务本 | Convenient tablet (pill) with evenly divided groove |
-
2005
- 2005-05-23 CN CN 200580016277 patent/CN1993111A/en active Pending
- 2005-05-23 CN CN2005800163652A patent/CN1960712B/en active Active
- 2005-05-23 CN CN 200580016367 patent/CN1960713A/en active Pending
- 2005-05-23 CN CN 200580016276 patent/CN1997331A/en active Pending
- 2005-05-23 CN CN2005800163667A patent/CN1964703B/en not_active Expired - Fee Related
-
2006
- 2006-12-19 ZA ZA200610682A patent/ZA200610682B/en unknown
- 2006-12-19 ZA ZA200610681A patent/ZA200610681B/en unknown
- 2006-12-19 ZA ZA200610683A patent/ZA200610683B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200610682B (en) | 2007-11-28 |
| CN1993111A (en) | 2007-07-04 |
| CN1960712A (en) | 2007-05-09 |
| CN1960713A (en) | 2007-05-09 |
| ZA200610683B (en) | 2007-11-28 |
| CN1964703A (en) | 2007-05-16 |
| CN1997331A (en) | 2007-07-11 |
| ZA200610681B (en) | 2007-12-27 |
| CN1960712B (en) | 2011-04-20 |
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